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Introduction: The proximal femur is a common site for primary sarcomas and metastatic lesions. Although the early results of tumor prostheses are promising, the long-term results of reconstruction are unknown. The purpose of this study is to evaluate the prognostic factors affecting prosthesis survival and complications after proximal femoral resection and reconstruction., Methods: We reviewed the results of 68 patients who underwent proximal femoral resection and reconstruction with a modular bipolar-type tumor prosthesis between 2005 and 2017. The mean follow-up was 55.6 months (range 6-172 months). There were 50 male and 18 female patients with a mean age of 41.5 years (range 11-80 years). Cumulative survival analysis was performed to analyze the risk factors of prosthesis survival. We also evaluated the complications after operation., Results: Fourteen (21%) patients required further surgery at a mean 37 months post-operatively (range 5-125 months). There were three cases of infection (4%), six of local recurrence (9%), three of acetabular erosion (4%) and two of stem loosening (3%). The implant survival rates were 83.9% at 5 years and 59.8% at 10 years. Prosthesis survivals did not differ based on fixation method (P = 0.085), age (P = 0.329) or resection length (P = 0.61). Acetabular chondrolysis was identified in 18 (26%) patients and longer resection length (≥20 cm) showed a trend for risk of acetabular wear (P = 0.132)., Conclusion: The results of proximal femoral resection and reconstruction with a modular bipolar-type prosthesis were found to be acceptable with infection and local recurrence as short-term complications and loosening and acetabular erosion as long-term complications., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background: Osteosarcoma (OS) is the most common primary bone tumor affecting humans and it has extreme heterogeneity. Despite modern therapy, it recurs in approximately 30-40% of patients initially diagnosed with no metastatic disease, with the long-term survival rates of patients with recurrent OS being generally 20%. Thus, early prediction of metastases in OS management plans is crucial for better-adapted treatments and survival rates. In this study, a radiomics model for metastasis risk prediction in OS was developed and evaluated using metabolic imaging phenotypes., Methods and Findings: The subjects were eighty-three patients with OS, and all were treated with surgery and chemotherapy for local control. All patients underwent a pretreatment 18F-FDG-PET scan. Forty-five features were extracted from the tumor region. The incorporation of features into multivariable models was performed using logistic regression. The multivariable modeling strategy involved cross validation in the following four steps leading to final prediction model construction: (1) feature set reduction and selection; (2) model coefficients computation through train and validation processing; and (3) prediction performance estimation. The multivariable logistic regression model was developed using two radiomics features, SUVmax and GLZLM-SZLGE. The trained and validated multivariable logistic model based on probability of endpoint (P) = 1/ (1+exp (-Z)) was Z = -1.23 + 1.53*SUVmax + 1.68*GLZLM-SZLGE with significant p-values (SUVmax: 0.0462 and GLZLM_SZLGE: 0.0154). The final multivariable logistic model achieved an area under the curve (AUC) receiver operating characteristics (ROC) curve of 0.80, a sensitivity of 0.66, and a specificity of 0.88 in cross validation., Conclusions: The SUVmax and GLZLM-SZLGE from metabolic imaging phenotypes are independent predictors of metastasis risk assessment. They show the association between 18F-FDG-PET and metastatic colonization knowledge. The multivariable model developed using them could improve patient outcomes by allowing aggressive treatment in patients with high metastasis risk., Competing Interests: The authors confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.

Purpose: Patients with high-grade osteosarcoma undergo several chemotherapy cycles before surgical intervention. Response to chemotherapy, however, is affected by intratumor heterogeneity. In this study, we assessed the ability of a machine learning approach using baseline 18 F-fluorodeoxyglucose ( 18 F-FDG) positron emitted tomography (PET) textural features to predict response to chemotherapy in osteosarcoma patients., Materials and Methods: This study included 70 osteosarcoma patients who received neoadjuvant chemotherapy. Quantitative characteristics of the tumors were evaluated by standard uptake value (SUV), total lesion glycolysis (TLG), and metabolic tumor volume (MTV). Tumor heterogeneity was evaluated using textural analysis of 18 F-FDG PET scan images. Assessments were performed at baseline and after chemotherapy using 18 F-FDG PET; 18 F-FDG textural features were evaluated using the Chang-Gung Image Texture Analysis toolbox. To predict the chemotherapy response, several features were chosen using the principal component analysis (PCA) feature selection method. Machine learning was performed using linear support vector machine (SVM), random forest, and gradient boost methods. The ability to predict chemotherapy response was evaluated using the area under the receiver operating characteristic curve (AUC)., Results: AUCs of the baseline 18 F-FDG features SUVmax, TLG, MTV, 1st entropy, and gray level co-occurrence matrix entropy were 0.553, 0538, 0.536, 0.538, and 0.543, respectively. However, AUCs of the machine learning features linear SVM, random forest, and gradient boost were 0.72, 0.78, and 0.82, respectively., Conclusion: We found that a machine learning approach based on 18 F-FDG textural features could predict the chemotherapy response using baseline PET images. This early prediction of the chemotherapy response may aid in determining treatment plans for osteosarcoma patients., Competing Interests: No potential conflicts of interest relevant to this article exist.

We compared the usefulness of Tc-methyl diphosphonate (Tc-MDP) bone scintigraphy and F-fluorodeoxyglucose (FDG) for positron emission tomography/computed tomography (PET/CT) in predicting histologic response in patients with osteosarcoma receiving neoadjuvant chemotherapy (NAC).We retrospectively reviewed 62 patients with high-grade osteosarcoma who had received 2 cycles of NAC and surgery. All patients underwent Tc-MDP bone scintigraphy and F-FDG PET/CT before and after NAC. Tc-MDP uptake in the primary tumor was measured quantitatively as the maximum tumor-to-nontumor ratio (T/NTmax) and F-FDG uptake was measured as the maximum standardized uptake value (SUVmax), before and after NAC. The percent changes of T/NTmax (percent changes of the maximum tumor-to-nontumor ratio [Δ%T/NTmax]) and SUVmax (percent changes of the maximum standardized uptake value [Δ%SUVmax]) after NAC were calculated and the correlations between these parameters were evaluated. After surgery, the effects of NAC were graded histopathologically (good vs poor) and the optimum cut-off values of Δ%T/NTmax and Δ%SUVmax for predicting histologic response were assessed using the receiver operating characteristic (ROC) curve analysis.Δ%T/NTmax and Δ%SUVmax were positively correlated with each other (r = 0.494, P < .01). Based on the ROC curve analysis, both Δ%T/NTmax (area under the curve [AUC] = .772, P < .01) and Δ%SUVmax (AUC = .829, P < .01) predicted good histologic response. However, there was no significant difference between the AUCs of Δ%T/NTmax and Δ%SUVmax (P = .44). The sensitivity and specificity for predicting good histologic response were 83.3% and 75.0%, for the criterion Δ%T/NTmax <-12.5%, and 80.0% and 81.3% for the criterion Δ%SUVmax <-49.0%, respectively.The Tc-MDP bone scan and F-FDG PET scan are non-inferior to each other in predicting the histologic response of osteosarcoma treatments. The Tc-MDP bone scan and F-FDG PET scan showed respective advantages with differing features. Therefore, physicians should consider which scan is appropriate for their own institute based on the advantages of each scan and the circumstances of the institute.

Background: Efficacy of gemcitabine and docetaxel (GEM + DOC) chemotherapy in patients with recurrent or refractory osteosarcoma was evaluated., Methods: Data of 53 patients from 9 institutions, who received GEM (675 or 900 mg/m(2) on days 1 and 8) and DOC (100 mg/m(2) on day 8), were retrospectively reviewed., Results: GEM + DOC was administered as adjuvant (n = 25) or palliative chemotherapy (n = 28). Patients received a median 3 courses (range, 1-10 courses). Objective response rate (CR + PR, where CR is complete response and PR is partial response) and disease control rate (CR+ PR + SD, where SD is stable disease) were 14.3% and 28.6%, respectively. Disease control rate was higher in patients receiving 900 mg/m(2) GEM than in patients receiving 675 mg/m(2) (50.0% vs. 12.5%, P = 0.03). Higher GEM dose was associated with better survival, both in adjuvant (1-year overall survival, 90.9 ± 8.7% vs. 38.5 ± 13.5%, P = 0.002) and palliative settings (50.0 ± 14.4% vs. 31.3 ± 11.6%, P = 0.04)., Conclusions: Further studies are necessary to investigate the efficacy of more aggressive and higher doses of GEM + DOC chemotherapy in osteosarcoma., (© 2016 Wiley Periodicals, Inc.)

Objectives: We evaluated the ability of dual-phase (18)F-FDG PET/CT to predict the histological response after neoadjuvant chemotherapy (NAC) in osteosarcoma., Methods: Thirty-one patients with osteosarcoma treated with NAC and surgery were prospectively enrolled. After injection of (18)F-FDG, both early (~60 min) and delayed (~150 min) PET were acquired before and after the completion of NAC. SUVmax, early/delayed SUVmax change (RImax), and early/delayed SUVmean change (RImean) of tumour were measured before (SUV1, RImax1, and RImean1) and after NAC (SUV2, RImax2, and RImean2). Then, we calculated the percentage changes between SUV1 and SUV2 (%SUV)., Results: Twelve patients (39%) exhibited good histological response after NAC. SUVmax, RImax, and RImean significantly decreased after NAC. Before NAC, only RImean1 predicted good histological response with the optimal criterion of < 10%, sensitivity of 92%, specificity of 57%, and accuracy of 71%. After NAC, %SUV, SUV2, and RImax2 predicted histological response. By using combined criterion of %SUV and RImax2 or SUV2 and RImean1 or SUV2 and RImax2, accuracies were 81%, 77%, and 77%, respectively., Conclusions: The histological response after NAC could be predicted by using RImean1 before the initiation of NAC in osteosarcoma. The combined use of SUV and RI values may provide a better prediction., Key Points: • Pretreatment dual-phase FDG-PET was useful to predict histological response in osteosarcoma. • A combination of early and delayed PET may increase the predictive value. • Early/delayed SUV change of tumours significantly decreased after neoadjuvant chemotherapy.

Background: We hypothesized that hemiarthroplasty with a synthetic device in skeletally immature patients with osteosarcoma around the knee would be functional due to high adaptability in the pediatric age group, and may decrease the number of surgeries until limb equalization by preserving the nearby physis., Methods: We analyzed the outcomes of 25 hemiarthroplasties (12 distal femur, 13 proximal tibia). Average patient age was 11.8 years. We assessed (1) whether hemiarthroplasty could be considered as a viable option and could preserve growth of the nearby physis, and (2) whether these patients could reach the final goal of adult-type tumor prosthesis implantation within a preplanned number of surgeries., Results: Three (12%) of 25 hemiarthroplasties showed failure. Average Musculoskeletal Tumor Society functional score of 23 patients was 25.1. Average tibial and femoral shortening for the corresponding reconstruction was 0.3 cm and 0.5 cm, respectively. In terms of number of surgeries for limb equalization, 19 patients (76%) had less, four (16%) had equal, and two (8%) had more surgeries than planned., Conclusions: Hemiarthroplasty is a sound option until skeletal maturity, allowing surgeons to choose the appropriate procedure based on the patient's growth status, and may reduce the amount of shortening by preserving nearby physis., (© 2015 Wiley Periodicals, Inc.)

Introduction: Low-grade osteosarcoma encompasses parosteal osteosarcoma (POS) and low-grade central osteosarcoma (LCOS), with LCOS more rare than POS. LCOS is also more likely to be misdiagnosed and inappropriately treated with an intralesional procedure, due to its misleading radiological features and the overlap of its pathological characteristics with those of benign bone tumors. Therefore, as a diagnostic adjunct for LCOS, immunohistochemical assay with murine double-minute type 2 (MDM2) and cyclin-dependent kinase 4 (CDK4) have been tried with controversial results. We investigated (1) the clinical course and surgical outcome of LCOS, and (2) the diagnostic role of immune-histochemical markers (CDK4, MDM2) and their correlation with clinico-radiologic findings., Materials and Methods: We retrospectively reviewed 16 LCOS patients with regard to age, gender, tumor location, plain radiographic pattern, tumor volume, extraosseous extension, initial diagnosis, initial treatment, definitive diagnosis, definitive treatment, surgical margins, histochemical markers, and oncological outcome., Results: Final survival status was continuous disease-free in 14, alive with disease in 1, and remaining 1 patient died of other cancer. Except for 1 patient who had not undergone excision of their primary lesion, no patients developed a local recurrence. Eight tumors (50%) showed diffuse immunostaining for CDK4. Three of 8 tumors labeled for CDK4 were also positive for MDM2. Six (75%) of 8 CDK4-positive tumors displayed lytic lesions on a plain radiograph; in contrast, 2 (33%) of 6 tumors showing a sclerotic pattern on a plain radiograph were positive for CDK4., Conclusions: The diagnosis of LCOS is challenging; however, if it is properly diagnosed, there is a high chance of a cure with wide excision alone. Positive immunostaining for CDK4 or MDM2 may be used as a diagnostic adjunct, although negative immunostaining cannot rule out this tumor. The clinical, radiological, and typical pathological findings are vital in raising the suspicion of this rare tumor.

Background: Extent of spontaneous necrosis in untreated osteosarcoma may imply tumor aggressiveness. Reports regarding this issue are scarce and there are several points to be clarified; (1) the correlation between tumor size and extent of spontaneous necrosis displayed was conflicting, (2) whether there is difference in necrosis rate between intra- and extra-medullary portion of tumor is not described, if it does, its relation with other clinico-pathologic variables, (3) in patients with surgical treatment only, >20 % spontaneous necrosis was a poor prognostic factor, however, whether that cutoff is still valid in chemotherapy cohort remains to be determined, (4) expected additional tumor necrosis by chemotherapy was made by simply comparing the necrosis rates of untreated and treated osteosarcoma cohort., Methods: We evaluated spontaneous necrosis in 43 osteosarcoma patients (39 Stage IIB, 4 Stage III). We evaluated overall necrosis rate and separately evaluated the necrosis rate of intra- and extra-medullary portion of tumor. These results were compared with other clinico-pathologic variables. To evaluate additional tumor necrosis induced by neoadjuvant chemotherapy, case (38 without preoperative chemotherapy)-control (76 with preoperative chemotherapy) study was performed., Results: The mean spontaneous necrosis rate was 23 %. Overall spontaneous necrosis was not associated with tumor volume. Necrosis rate of extramedullary tumors was higher in cases of large tumors (p = 0.02). In patients with upfront surgery followed by chemotherapy, 5-year event-free survival rate of patients with >20 and <20 % spontaneous necrosis were 82 ± 17 and 79 ± 18.5 %, respectively (p = 0.75). After chemotherapy, regardless of tumor volume and location, control group tumors showed an increase in the tumor necrosis of approximately 50 %., Conclusion: In chemotherapy era, the extent of spontaneous necrosis has no relation with survival. The expected additional tumor-killing effect of preoperative chemotherapy is around 50 % of initial tumor volume.

Purpose: We evaluated the potential of sequential fluorine-18 fluorodeoxyglucose ((18) F-FDG) positron emission tomography (PET)/computed tomography (CT) and MRI (PET/MRI) after one cycle of neoadjuvant chemotherapy to predict a poor histologic response in osteosarcoma., Methods: A prospective study was conducted on 30 patients with osteosarcoma treated with two cycles of neoadjuvant chemotherapy and surgery. All patients underwent PET/MRI before, after one cycle, and after the completion of neoadjuvant chemotherapy, respectively. Imaging parameters [maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and tumor volume based on magnetic resonance (MR) images (MRV)] and their % changes were calculated on each PET/MRI data set, and histological responses were evaluated on the postsurgical specimen., Results: A total of 17 patients (57%) exhibited a poor histologic response after two cycles of chemotherapy. Unlike the little volumetric change in MRI, PET parameters significantly decreased after one and two cycles of chemotherapy, respectively. After one cycle of chemotherapy, SUVmax, MTV, and TLG predicted the poor responders. Among these parameters, either MTV ≥ 47 mL or TLG ≥ 190 g after one cycle of chemotherapy was significantly associated with a poor histologic response on multivariate logistic regression analysis (OR 8.98, p = 0.039). The sensitivity, specificity, and accuracy of these parameters were 71%, 85% and 77%; and 71%, 85% and 77 %, respectively., Conclusion: The histologic response to neoadjuvant chemotherapy in osteosarcoma can be predicted accurately by FDG PET after one course of chemotherapy. Among PET parameters, MTV and TLG were independent predictors of the histologic response.

Background: We assessed the plain radiographic characteristics of 10 cases of osteosarcomas during the initial painful period that had been overlooked by a primary physician. In addition, we evaluated chronologic changes in radiographic findings from initial symptomatic period to the time of accurate diagnosis., Methods: The clinical records were reviewed for clinical parameters including age, sex, location, presenting symptoms, initial diagnosis, duration from initial symptoms to definite diagnosis, and initial and follow-up plain radiographic findings of the lesion., Results: Initial clinical diagnoses included a sprain in 6, growing pain in 2, stress fracture in 1, and infection in 1 patient. Initial plain radiographic findings were trabecular destruction (100%), cortical disruption (60%), periosteal reaction (60%), and soft tissue mass (10%). Intramedullary matrix changes were osteosclerosis in 6 and osteolysis in 4 patients. On progression, 4 cases with minimal sclerosis changed to osteoblastic lesion in 3 patients and osteolytic lesion in 1. Four cases with faint osteolytic foci transformed into osteolytic lesion in 3 and mixed pattern in 1., Conclusions: Notable plain radiologic findings of incipient-stage osteosarcoma include trabecular disruption along with faint osteosclerosis or osteolysis. In symptomatic patients with trabecular destruction, additional imaging study including magnetic resonance imaging should be performed to exclude osteosarcoma in the incipient phase, even without radiologic findings suggesting malignant tumor, such as cortical destruction or periosteal reaction.

Background: Primary tumor growth during neoadjuvant chemotherapy is believed to be a sign of resistance to chemotherapy (chemoresistance), and often is associated with poor histologic response, local recurrence, and poorer survival. Currently there are no proven indicators to predict poor response to chemotherapy at the time of diagnosis., Questions/purposes: We asked (1) what clinicopathologic factors present at diagnosis predict primary tumor growth during neoadjuvant chemotherapy, (2) what factors at presentation predict survival, and (3) when the factors at presentation and the treatment-related factors are considered, what factors independently correlate with survival., Methods: We studied 567 patients with Stage IIB osteosarcomas. The factors assessed included age, sex, location, pattern on plain radiographs (radiodense, radiolucent, mixed), MRI findings, pathologic subtype, initial tumor volume determined by MRI, tumor volume change after chemotherapy, surgical margin, and histologic response to preoperative chemotherapy. Logistic modeling was used to identify risk factors., Results: Independent risk factors associated with primary tumor growth after neoadjuvant chemotherapy were proximal tumor location (p < 0.01; relative risk [RR], 2.41; 95% CI, 1.5-3.86) and fluid-fluid level on initial MRI (p < 0.01; RR, 5.56; 95% CI, 3.48-8.87). Among factors at presentation, large initial tumor volume (p < 0.01; RR, 1.58; 95% CI, 1.22-2.04), proximal tumor site (p < 0.01; RR, 1.61; 95% CI, 1.19-2.19), and presence of fluid-fluid level (p < 0.01; RR, 1.83; 95% CI, 1.37-2.5) independently predicted reduced event-free survival. When we consider the factors at presentation and treatment-related factors, large initial tumor volume (p < 0.01; RR, 1.54), tumor growth after neoadjuvant chemotherapy (p < 0.01; RR, 3.88), inadequate surgical margin (p < 0.01; RR, 2.42), and poor histologic response (p = 0.03; RR, 1.43) were independent poor prognostic factors of event-free survival., Conclusions: Proximal tumor location and the presence of the fluid-fluid level on initial MRI were predictors of tumor progression and poor survival in patients presenting with Stage IIB osteosarcomas. If confirmed in other studies, patients with these risk factors should be considered for trials of other treatment strategy., Level of Evidence: Level III, prognostic study. See the Instructions for Authors for a complete description of levels of evidence.

Background: The presence of fluid-fluid levels (FFLs) on osteosarcoma magnetic resonance imaging (MRI) is underestimated as a nonspecific finding; however, we hypothesized that FFL in conventional osteosarcoma may be indicative of chemoresistance., Methods: In 567 stage IIB osteosarcoma patients, we evaluated the following: the incidence of FFL and their correlation with other clinicopathological variables; tumor volume change after chemotherapy and survival according to the presence of FFL; and the relationship between survival and the extent of FFL., Results: One hundred eight (19 %) tumors showed FFL on initial MRI. FFL were correlated with proximal humeral location (P = 0.017), osteolytic on plain radiographs (P < 0.001), tumor enlargement after chemotherapy (P < 0.001), and poor histological response (P = 0.005). Large tumor (P < 0.01), proximal tumor location (P = 0.01), and presence of FFL (P < 0.01) were independent predictors of poor survival. Compared to the extensive FFL (more than one third of the tumor), small foci of FFL (less than one third of the tumor) showed a high tendency for tumor enlargement after chemotherapy (P < 0.001), poor histologic response (P = 0.001), and worse survival (P < 0.001)., Conclusions: FFL on initial MRI could predict tumor progression after chemotherapy. Notably, tumors with small foci of FFL (less than one third of the tumor) have a high propensity for poor outcome. Patients with this finding should be considered for risk-adapted therapy.

Background: Tumor enlargement after chemotherapy is a predictor of a poor histological response, poor survival, and local recurrence. However, the cutoff point of tumor enlargement for predicting subsequent oncologic events has not been determined., Methods: We retrospectively reviewed 567 patients who were treated at our institute for stage IIB osteosarcoma. We used receiver operating characteristic (ROC) curve analysis of tumor volume increase for the prediction of subsequent metastasis or local recurrence, and calculated diagnostic indices for different cutoff values., Results: A tumor volume increase of >15% predicted subsequent metastasis or local recurrence with a sensitivity of 64.7%, a specificity of 81.5%, a positive predictive value of 71.6%, and a negative predictive value of 76.1%. Increases in tumor volumes based on this cutoff value were able to predict subsequent oncologic events in all clinical subgroups, except in cases of rare pathologic subtypes. However, for tumors in the proximal humerus, a cutoff value of 25% had optimal predictive value., Conclusions: This study shows that a cutoff value of 15% for tumor volume increase is useful for predicting subsequent metastasis or local recurrence. Our results suggest that tumor enlargement after chemotherapy serves as an easily assessable clinical parameter for risk-adapted therapy., (© 2013 Wiley Periodicals, Inc.)

Objective: We compared the diagnostic performance of (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) and (99 m)Tc-methylene diphosphonate bone scintigraphy (BS) for the detection of bone metastasis in osteosarcoma., Materials and Methods: We retrospectively reviewed 206 patients with stage II-IV osteosarcoma treated with surgery and chemotherapy as well as at least one paired PET/CT and BS scan (defined as an examination). PET/CT and BS images were interpreted separately. When analyzing the diagnostic yield of a combination of PET/CT and BS (PET/CT+BS), an examination was considered positive if either PET/CT or BS scored positive. The final diagnosis was obtained from histological findings or clinical follow-up with imaging studies for at least 6 months. Diagnostic performances of PET/CT, BS, and their combinations were calculated., Results: Out of 833 examinations in 206 patients, 55 with 101 lesions in 38 patients were confirmed as bone metastases. The sensitivity, specificity, and diagnostic accuracy were 95, 98, and 98%, respectively, for PET/CT; 76, 97, and 96%, respectively, for BS; and 100, 96, and 97%, respectively, for PET/CT+BS in an examination-based analysis. Lesion-based analysis demonstrated that the sensitivity of PET/CT+BS (100%) was significantly higher than that of PET/CT (92%) or BS (74%) alone. BS detected significantly less bone metastases in the growth plate region than outside the growth plate region (22 vs. 77%)., Conclusions: PET/CT is more sensitive and accurate than BS for diagnosing bone metastases in osteosarcoma. The combined use of PET/CT and BS improves sensitivity.

Background: The relationship between surgical margin and local recurrence (LR) in osteosarcoma patients with poor responses to chemotherapy is unclear. Moreover, the incidences of LR according to three different resection planes (bone, soft tissue, and perineurovascular) are not commonly known., Methods: We evaluated the incidence of LR in three areas. To assess whether there is a role of surgical margin on LR in patients resistant to preoperative chemotherapy, we designed a case (35 patients with LR) and control (70 patients without LR) study. Controls were matched for age, location, initial tumor volume, and tumor volume change during preoperative chemotherapy., Results: LR occurred at the soft tissues in 18 cases (51.4%), at the perineurovascular tissues in 11 cases (31.4%), and at the bones in six cases (17.2%). The proportion of inadequate perineurovascular margin was higher in the case group than in the control group (p = 0.01). Within case-control group (105 patients), a correlation between each margin status and LR at corresponding area was found in the bone (p < 0.001) and perineurovascular area (p = 0.001)., Conclusions: LR is most common in soft tissues. In patients showing similar unfavorable responses to chemotherapy, the losses of perineurovascular fat plane on preoperative magnetic resonance imaging may be a valuable finding in predicting LR.

Unlabelled: We evaluated the potential of (18)F-FDG PET/CT and diffusion-weighted imaging (DWI) to monitor the histologic response in patients with extremity osteosarcoma receiving neoadjuvant chemotherapy, using sequential PET/CT and MR imaging., Methods: We prospectively registered 28 patients with high-grade osteosarcoma treated with 2 cycles of neoadjuvant chemotherapy and surgery. All patients underwent sequential (18)F-FDG PET/CT and MR imaging before (PET/MR1) and after neoadjuvant chemotherapy (PET/MR2). Maximum standardized uptake value (SUV), tumor volume based on MR imaging (MRV), and the mean apparent diffusion coefficient (ADC) values were measured on PET/MR1 (SUV1, MRV1, and ADC1) and PET/MR2 (SUV2, MRV2, and ADC2). The percentage changes in maximum SUV (ΔSUV), MRV (ΔMRV), and ADC (ΔADC) were calculated, and the correlations among these parameters were evaluated. After surgery, the effects of neoadjuvant chemotherapy were graded histopathologically: grades III and IV (necrosis of ≥ 90%) indicated a good response, and grades I and II (necrosis of < 90%) indicated a poor response. The optimum cutoff values of ΔSUV, ΔMRV, ΔADC, and their combination for predicting histologic response were assessed by single- and multi-receiver-operating-characteristic curve analysis., Results: Twenty-seven patients were enrolled in the present study after 1 patient with inadequate acquisition of MR imaging was excluded. ΔSUV and ΔADC negatively correlated with each other (ρ = -0.593, P = 0.001), and ΔMRV did not correlate with ΔSUV or ΔADC. The cutoff value, sensitivity, specificity, and accuracy for predicting good histologic response were ≤ -52%, 67%, 87%, and 78%, respectively, for ΔSUV and > 13%, 83%, 73%, and 78%, respectively, for ΔADC. However, ΔMRV did not predict histologic response. Sensitivity, specificity, and accuracy were 83%, 87%, and 85%, respectively, using the combined criterion of ΔSUV ≤ -31% and ΔADC > 13%., Conclusion: In the current preliminary study, both PET/CT and DWI are useful for predicting histologic response after neoadjuvant chemotherapy in osteosarcoma. Combining PET/CT and DWI may be an effective method to predict the histologic response of patients to neoadjuvant chemotherapy.

Purpose: This study evaluated the usefulness of the maximum standardized uptake value (SUVmax) as a measure of histologic response to neoadjuvant chemotherapy in patients with extremity osteosarcoma. The correlation between [(18) F]FDG PET SUVmax values and histologic response to preoperative chemotherapy was also assessed prospectively using PET/MRI., Methods: A total of 26 consecutive patients with high-grade osteosarcoma were prospectively enrolled. All patients underwent parallel PET and MRI scans before and after neoadjuvant chemotherapy. Using the PET and MRI images and pathologic mapping, we assessed the percentage necrosis by histology at the highest metabolic activity point in the tumors. This was defined as the minimum histologic response. The predictive values of SUVmax before (SUV1) and after (SUV2) chemotherapy and the SUV change ratio were determined. Correlations were also investigated among SUV2, minimum histologic response and histologic response., Results: Histologically, 13 patients were classified as good responders and 13 as poor responders. Patients with an SUV2 of >5 showed a poor histologic response. A significant correlation was found between SUV2 and histologic response (Spearman's rho -0.642; P < 0.001), and SUV2 and histologic response were both found to be significantly correlated with minimum histologic response (Spearman's rho -0.515 and 0.911; P = 0.007 and P < 0.001, respectively)., Conclusion: A SUVmax of more than 5 after neoadjuvant chemotherapy identified the majority of histologic nonresponders (sensitivity 61.3 %, PPV 88.9 %). Tumor necrosis at the point of maximum metabolic activity was found to be significantly correlated with the histologic response of entire resected specimen.

Background: Tumor enlargement after chemotherapy is considered one of the high-risk factors for local recurrence and survival in osteosarcoma. We hypothesized patients with this risk factor will have similar survival regardless of the development of local recurrence., Questions/purposes: We asked (1) the prognostic factors for survival in our cohort, (2) how much effect local recurrence has on survival among patients with similar preoperative risk factors, and (3) what prognostic factors are important for survival in these selected patients., Methods: We analyzed the prognostic factors for survival in 449 patients with extremity osteosarcoma without metastatic disease at initial diagnosis and treatment (38 with local recurrence, 411 without local recurrence). We compared the survival difference between patients with local recurrence (n = 38) and without local recurrence (control, n = 76) matched for age, location, initial tumor volume, and tumor volume change after chemotherapy, and assessed prognostic factors in this subgroup., Results: In a cohort study, multivariate analysis revealed initial tumor volume, tumor enlargement, inadequate margin, and local recurrence predicted poor survival. In the case-control study, the 10-year metastasis-free survival rates of two groups were 13.1 ± 10.7% and 19.3 ± 9%, respectively. In the case-controlled groups, tumor enlargement and initial tumor volume showed multivariate significance., Conclusions: Local recurrence has a small impact on survival in patients with high-risk osteosarcoma., Level of Evidence: Level III, prognostic study. See Guidelines for Authors for a complete description of levels of evidence.

Background: Known risk factors (surgical margin, tumor necrosis) of local recurrence (LR) in osteosarcoma are determined by results available after surgery. However, relations between preoperative characteristics and LR have not been clearly defined., Methods: We compared the clinicopathologic characteristics of 36 osteosarcoma patients with LR and 394 patients without LR after surgery. In addition, prognostic variables were evaluated to establish factors could influence LR., Results: Compared to the non-LR group, the LR group showed an increase in tumor volume ratio (TVR) during preoperative chemotherapy (P < 0.01), inadequate surgical margin (P < 0.01), and poor histologic response (P < 0.01). Univariate analysis of data from 430 patients revealed that an increased TVR (P < 0.01), inadequate surgical margin (P < 0.01), poor histologic response (P < 0.01), and nonosteoblastic pathologic subtype (P = 0.04) were negatively related to LR-free survival. In multivariate analysis, an elevated TVR (P < 0.01, relative risk = 10.26) and inadequate surgical margin (P < 0.01, relative risk = 5.91) emerged as the key prognostic factors for LR., Conclusions: A TVR increase during preoperative chemotherapy could be used to predict patients at high risk of LR. This finding might be useful when considering surgical options to decrease the risk of LR.

Background: The receptor activator of nuclear factor κB ligand (RANKL/TNFSF11) is expressed in metastatic bone cancer cells and has been suggested to play a key role in cell migration and metastatic behavior. We determined whether RANKL expression is correlated to clinical behavior of localized, high-grade osteosarcoma., Patients and Methods: This retrospective, immunohistochemical study was performed using materials obtained from 40 patients treated at Korea Cancer Center Hospital between 1995 and 2007. Prechemotherapy biopsy samples were stained for RANKL and correlations between RANKL expression and clinical characteristics and outcomes were evaluated. Staining was interpreted in a semiquantitative manner using an intensity based scoring system., Results: Thirty cases (75.0%) stained positively for RANKL; 15 (50.0%) had a high RANKL score (≥ 4) and the other 15 a low RANKL score (≤3). RANKL expression and RANKL scores were not related to age, sex, tumor location, tumor volume, or pathologic subtype. However, RANKL expression was related to a poor response to preoperative chemotherapy (P = 0.03) and a high RANKL score was associated with inferior survival. The 5-year event-free survival of patients with RANKL score ≥4 was 17.8 ± 10.5%, which was far worse than those with RANKL scores 1-3 or 0 (50.0 ± 15.8%, 56.0 ± 13.7%, respectively, P = 0.02)., Conclusions: The RANKL-RANK-OPG axis might be a promising target for the treatment of osteosarcoma, but further studies are needed to verify our data in a larger cohort., (Copyright © 2011 Wiley-Liss, Inc.)

Background: The purpose of this study is to evaluate the risk of subsequent local recurrence (LR) and survival of parosteal osteosarcoma (POS) patients who underwent re-excision after intralesional excision., Methods: We analyzed clinical outcomes of 11 POS patients referred after intralesional excision. Average follow-up was 86 months (range: 37-190 months). There were 9 Stage IB lesions and 2 Stage IIB lesions. Tumors were located in the femur (3) and in other locations (8). Seven patients showing recurrent tumor at referral received entire segmental excision while remaining four patients without LR underwent hemi-cortical excision., Results: The 5-year metastasis free survival rate of 11 patients was 81.8%. Patients without evident tumor mass did not show further recurrence after re-excision. However, 5 (71.4%) of the 7 patients with recurrent tumor relapsed despite segmental re-excision, and their median interval to subsequent LR was 18.8 months (range: 4-9 months). Two of five patients with re-recurrence developed metastases which were unresponsive to chemotherapy., Conclusions: Following inadvertent intralesional procedure, re-excision should be liberally applied before there is an evidence of recurrence. In patients presenting with gross LR, amputation should not be spared unless wide surgical margin can be achieved., (Copyright © 2010 Wiley-Liss, Inc.)

Background: Patients with malignant fibrous histiocytoma of bone (MFH-B) and osteosarcoma reportedly have comparable survival rates, despite the lesser chemosensitivity of patients with MFH-B compared with those with osteosarcoma., Questions/purposes: We therefore asked (1) whether there is a difference in the initial tumor volume, histologic response, and survival between cohorts with MFH-B and osteosarcoma, and (2) whether histologic responses and survival rates differed between two groups even after matching for volume and age., Patients and Methods: We retrospectively compared 27 patients with Stage IIB MFH-B with 389 patients with localized osteosarcoma for initial tumor volume, age, histologic response, and survival. We compared histologic response and survival between 27 patients with MFH-B and 54 patients with osteosarcoma matched for tumor volume and age., Results: MFH-B occurred more frequently in older patients and they presented with a smaller mean tumor volume and more frequent osteolytic pattern when compared with patients with osteosarcoma. The 5-year metastasis-free survival rates of the MFH-B and osteosarcoma groups were similar: 61.2% ± 9.7% and 61.3% ± 2.5%, respectively. We observed similar proportions of good responders to chemotherapy in the two groups, and the 5-year metastasis-free survival rates were 61.2% ± 9.7% and 70.4% ± 6.2%, respectively., Conclusions: Patients with MFH-B and osteosarcoma have similar survival rates and histologic responses to chemotherapy. Although MFH-B and osteosarcoma differ in clinical presentation, their response pattern to contemporary therapy is similar., Level of Evidence: Level III, prognostic study. See the Guidelines for Authors for a complete description of levels of evidence.

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.

Background and Objectives: The poor prognosis of pelvic osteosarcoma is well recognized, but the cause of this prognosis has not been well defined., Methods: We analyzed the clinicopathologic characteristics of pelvic osteosarcoma, and their prognostic significances in a cohort of 41 patients, treated either surgically by ablation or non-surgically. In a separate case-controlled study, the 20 surgically treated osteosarcoma patients were matched with 38 patients with extremity osteosarcoma by tumor volume and age., Results: The 5-year overall survival rates of the surgically and the non-surgically treated pelvic osteosarcoma were 55.8 +/- 13.0% and 4.8 +/- 4.7%, respectively (P < 0.01). Non-surgically managed pelvic osteosarcoma group were found to have a larger tumor volume (P = 0.02), bladder displacement and sacroiliac joint involvement (P < 0.01). The 5-year metastasis free survival rates in the surgically treated pelvic and extremity osteosarcoma were no different (41.4 +/- 12.8% vs. 48.6 +/- 8.4%), and histologic responses to chemotherapy were similar in two groups., Conclusions: No significant difference in survival or histologic response was found between the surgically treated pelvic and the extremity osteosarcoma with suitable tumor volume. Outcome of pelvis osteosarcoma corresponds to the poor survival of extremity osteosarcoma of high initial tumor burden.

Background: Although there are controversies about the prognosis of proximal humeral osteosarcoma, our previous study showed poor survival in those patients. In the present study, we undertook to determine why this site is associated with a poor outcome and to identify the clinicopathologic variables involved., Methods: The study cohort consisted of 36 proximal humeral and 341 other extremity American Joint Committee on Cancer (AJCC) stage II osteosarcomas. We examined the clinicopathologic differences between these osteosarcomas. The prognostic significances of factors identified for a proximal humoral location were evaluated by survival analysis of all 377 patients., Results: Patients with a proximal humeral osteosarcoma had the following characteristics: a higher incidence of pathologic fracture (P\0.01), an osteolytic pattern on plain radiographs (P\0.01), an unusual pathological subtype (P = 0.01), poor histologic response (P\0.01), and an increased tumor-volume ratio (TVR) (P\0.01). Multivariate analysis revealed that a large tumor volume (P\0.01), an increase in tumor volume (P\0.01), and a poor histologic response to preoperative chemotherapy (P\0.01) independently predicted shorter metastasis-free survival., Conclusions: The association between proximal humeral osteosarcoma and poor survival could be the result of unresponsiveness to chemotherapy, which was expressed by a tumor volume increase in our patients.

Objective: We aimed to understand the biology of osteosarcoma of the flat bone, which is a rare tumor entity., Methods: Cases with osteosarcoma of the flat bone were compared with those of the extremity in order to evaluate their clinicopathologic characteristics. And the influences of heterogeneous treatment modalities on outcome were analyzed., Results: Tumors of the flat bone comprised 91 (11.3%) of 806 osteosarcoma cases. Eight cases were secondary osteosarcoma associated with previous radiotherapy. Patients with a flat bone tumor were significantly older and more likely to present with metastases at diagnosis than extremity tumor. The proportions of female sex and chondroblastic subtype were higher among flat bone tumors than among extremity tumors. The 5-year overall survival and event-free survival rates were 35.2 +/- 5.4% and 24.7 +/- 5.5%, respectively. Although age and histologic response to pre-operative chemotherapy were not related to outcome of flat bone tumors, treatment modality influenced the survival. Patients treated surgically had better outcomes than those treated by another means. Radiation therapy did not appear to be an effective local control measure as surgery., Conclusions: Treatment outcome of the tumor of the flat bone was worse than extremity tumors. Further studies are needed to identify effective local control measures that can substitute for surgery and to determine the biologic characteristics of osteosarcoma of the flat bone.

Background: Little is known about the clinical outcome or prognosis of diaphyseal osteosarcoma treated with modern therapeutic strategies., Methods: We conducted both cohort (n=400) and case-control (n=102) studies on 34 American Joint Committee on Cancer stage II diaphyseal osteosarcomas of the extremities., Results: In the cohort study, 34 patients with a diaphyseal osteosarcoma showed significantly better survival than 366 patients with metaphyseal osteosarcoma (5-year metastasis-free survival rates, 87% for cases vs. 59% for controls, P=0.01; 5-year overall survival rates, 90% for cases vs. 71% for controls, P=0.04). The case-control study conducted on 34 patients with diaphyseal osteosarcoma and 68 controls (recruited from among the 366 patients with metaphyseal osteosarcoma by matching for age, tumor volume, and location) showed no survival difference between cases and controls (5-year metastasis- free survival rates, P=0.07; 5-year overall survival rates, P=0.26)., Conclusions: Location differences between the diaphysis and metaphysis may have no prognostic relevance.

Background: Unplanned primary surgery has been known to have a negative prognostic impact in osteosarcoma., Methods: We identified 20 osteosarcoma patients that had undergone inadvertent surgery followed by adequate treatment without delay, and compared the clinicopathologic characteristics of these 20 case patients with those of 365 patients who underwent incisional biopsy. For survival analysis, 40 control patients matched for tumor size at presentation, tumor location, age and gender were selected from these 365 patients., Results: Unusual initial clinicopathologic characteristics were frequently observed in the case patients, such as, an older age, a small tumor size, an unusual tumor location, and a lytic radiographic pattern. The 5-year overall survival rate in the case group was 89.4 +/- 7.1% and in the control group was 83.9 +/- 6.1%, and the 5-year event-free survival rate in the case group was 90.0 +/- 6.7% and in the control group was 76.8 +/- 6.8%. The log rank test revealed no survival difference between the case and control groups., Conclusions: As is the case for soft tissue sarcoma, inadvertent extensive curettage with no ensuing treatment delay was found to have no detrimental effect on overall- or event-free survival in osteosarcoma. Further study using a larger sample size is needed to confirm our results.

Introduction: In this retrospective study, we evaluated to what extent diagnostic delays impact prognosis in osteosarcoma., Materials and Methods: The authors identified 26 osteosarcoma patients who had undergone inappropriate procedure-associated diagnostic delays of more than 45 days after surgery, calculated overall survival rates, and analyzed clinicopathologic characteristics., Results: Initial clinical impressions were of a benign bone tumor in 15 patients, fracture in 8, and infection in 3. After initial inappropriate procedures, primary surgeons failed to send a tissue sample to a pathologist for definite diagnosis in 12 cases, and pathologists made incorrect diagnoses in the other 14. The average doctor-associated diagnostic delay after inappropriate surgery for these 26 patients was 10.5 months. Following referral to our institute, 22 underwent both surgery and chemotherapy and the remaining 4 patients underwent chemotherapy only. Four of the 26 patients were alive at last follow-ups. Estimated 5- and 10-year overall survival rates were 26 and 10%, respectively., Conclusions: The present study shows that doctor-associated diagnostic delay superimposed on an inappropriate primary procedure has a significant detrimental effect on overall survival in osteosarcoma. This study demonstrates that surgeons and pathologists should spare no effort to minimize diagnostic errors and delays.

Unlabelled: Response to neoadjuvant chemotherapy is a significant prognostic factor for osteosarcoma; however, this information can be determined only after surgical resection. If we could predict histologic response before surgery, it might be helpful for the planning of surgeries and tailoring of treatment. We evaluated the usefulness of (18)F-FDG PET for this purpose., Methods: A total of 70 consecutive patients with a high-grade osteosarcoma treated at our institute were prospectively enrolled. All patients underwent (18)F-FDG PET and MRI before and after neoadjuvant chemotherapy. We analyzed the predictive values of 5 parameters, namely, maximum standardized uptake values (SUVs), before and after (SUV2) chemotherapy, SUV change ratio, tumor volume change ratio, and metabolic volume change ratio (MVCR) in terms of their abilities to discriminate responders from nonresponders., Results: Patients with an SUV2 of less than or equal to 2 showed a good histologic response, and patients with an SUV2 of greater than 5 showed a poor histologic response. The histologic response of a patient with an intermediate SUV2 (2 < SUV2

Introduction: In this retrospective study, we assessed tumor growth patterns as visualized on MR images, and examined whether tumor growth patterns correlate with clinicopathologic variables. In addition, we also evaluated the relationship between patient outcome and tumor growth pattern in the whole study cohort and in subsets of AJCC IIA and IIB patients., Materials and Methods: We retrospectively reviewed 347 patients with Enneking stage IIB and AJCC stage II osteosarcoma that was treated with surgery and neoadjuvant chemotherapy at our institute. Patients were divided into three groups based on tumor growth pattern, namely, concentric, eccentric, and longitudinal groups. Fisher's exact test was performed to analyze correlations between tumor growth patterns and clinicopathological variables. Five-year metastasis-free survival and overall survival were evaluated using univariate and multivariate analyses., Results: In terms of tumor growth patterns, 225 patients (64.8%) had a concentric, 71 (20.5%) an eccentric and 51 (14.7%) a longitudinal tumor. Eccentric tumors were usually small and responded well to chemotherapy, whereas concentric tumors were large and responded poorly. The prognostic significances of tumor growth patterns were confirmed by univariate and multivariate analyses. Among AJCC stage IIA patients, no survival difference was found according to growth pattern, whereas in AJCC stage IIB patients, longitudinal tumors were associated with significantly better survival than concentric tumors., Conclusions: Tumor growth pattern was found to be an independent prognostic factor in stage II osteosarcoma. Moreover, longitudinally growing tumors were associated with better survival in AJCC stage IIB patients. Our results suggest that tumor growth pattern could be used as an indicator of risk-adapted therapy when combined with other prognostic factors.

Background: We assessed volume changes after neoadjuvant chemotherapy and evaluated relations between tumor size changes and clinical characteristics. In addition, we sought to determine whether tumor size change influences patient outcome., Methods: The records of 127 patients with stage II osteosarcoma who showed more than a 15% volume change after chemotherapy were retrospectively reviewed. Patients were divided into two groups depending on whether tumors increased or decreased in size. Fisher's exact test was performed to analyze correlations between tumor size changes and clinicopathological variables. Five-year metastasis-free survival and overall survival were evaluated using univariate and multivariate analyses., Results: A total of 71 patients (55.9%) showed a decrease in tumor volume, and 56 patients (44.1%) showed an increase. An increase in tumor volume after neoadjuvant chemotherapy was found to be positively correlated with a poor histological response and subsequent metastasis. Univariate analysis identified the following parameters as poor prognostic factors: age < or = 15 years (P = 0.03), American Joint Committee on Cancer (AJCC) stage IIB (P = 0.02), a subtype other than osteoblastic (P < 0.01), a poor histological response (P < 0.001), and increased tumor volume after preoperative chemotherapy (P < 0.0001). Multivariate analysis revealed that AJCC stage IIB (P = 0.006) and an increase in tumor volume after preoperative chemotherapy (P < 0.001) both independently shortened metastasis-free survival. However, a poor histological response lost its prognostic significance (P = 0.34)., Conclusions: Increased tumor volume after neoadjuvant chemotherapy independently shortened metastasis-free and overall survival in AJCC stage II osteosarcoma patients. Tumor volume changes may serve as a basis for risk-adapted therapy when used in combination with other prognostic factors.

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 >or=40 or 12-14 (female) or 13-15 (male), "0" for other ages; MTL (cm); "2" for >or=8, "1" for 6-8, "0" for

The clinical impact of postoperative deep infection on survival remains controversial in osteosarcoma patients. The authors identified 31 osteosarcoma patients that developed a deep infection within 1 year of operation between 1990 and 2003, and compared clinicopathologic characteristics of 31 patients that developed an infection with those of 316 patients that did not. For survival analysis, 62 noninfected patients matched for prognostic factors such as histologic response, tumor size, and location were also selected. In infected patients, although it was not significant due to the small patient numbers, good response to preoperative chemotherapy and a proximal tibial location were frequently observed. No local recurrence developed in infected patients. Five-year overall and metastasis-free survival rates for the 31 infected patients were as high as 89% and 73%, respectively. However, after matching for clinical factors, no survival difference was noted between infected and noninfected patients. Deep infection has a multifaceted effect on patients. However, the present study suggests that the reported positive effect on survival is likely to be related to the clinical characteristics of infected patients rather than an antitumor effect due to the infection. Further investigations are needed to clarify the precise effects of infection.

Background: In the revised AJCC staging system a maximal tumor diameter of 8 cm was adopted as a cutoff for the subdivision of IIA and IIB osteosarcoma, but this cutoff was chosen based on limited information., Methods: We retrospectively reviewed 347 patients with stage II osteosarcoma that were treated at our institute. We plotted a receiver operating characteristic (ROC) curve of maximal tumor diameter for the prediction of subsequent metastasis, and calculated diagnostic indices according for different cutoffs., Results: A maximal tumor diameter greater than 8 cm was found to predict subsequent metastasis with a sensitivity of 76.3%, a specificity of 49.5%, and a positive predictive value of 49.0% Almost half of stage IIB patients subsequently developed metastasis, whereas only a quarter of stage IIA patients did so. Tumor size had no prognostic relevance for proximal humeral tumors., Conclusions: The present study shows that an 8 cm maximal tumor diameter cutoff is useful for subdividing AJCC stage II osteosarcoma patients in terms of predicting of a subsequent metastatic event. Our results suggest that the IIA and IIB subdivision in the AJCC staging system provides a basis for risk-adapted therapy when used in combination with other prognostic factors., ((c) 2008 Wiley-Liss, Inc.)

Objective: In this retrospective study, we assessed the plain-film radiographic patterns of American Joint Committee on Cancer (AJCC) stage II osteosarcoma and analyzed the relationship between these patterns and clinicopathologic variables., Materials and Methods: We retrospectively reviewed 347 patients with AJCC stage II osteosarcoma who were treated at our institute. Patients were divided into three groups based on radiographic patterns, i.e., osteoblastic, osteolytic, and mixed. Fisher's exact chi-square test was performed to analyze correlations between radiographic patterns and clinicopathological variables., Results: One hundred and eighty-eight patients had an osteoblastic tumor, 101 had an osteolytic tumor, and 58 had a mixed tumor. Tumors with an osteoblastic pattern showed a tendency to have the following characteristics: AJCC stage II-B, osteoblastic or chondroblastic subtype, and no pathologic fracture. Conversely, osteolytic tumors were frequently of AJCC stage II-A, had a fibroblastic or rare subtype, and were associated with a pathologic fracture. Finally, mixed tumors were frequently found in men. No survival difference was found according to radiographic pattern., Conclusions: Plain-film radiographic patterns were found to be related with clinicopathological features. We believe that it could be used to provide valuable information for treatment decision-making in cases of high-grade extremity osteosarcoma.

The medical records of 241 children with stage II osteosarcoma were reviewed to assess whether growth characteristics at the time of diagnosis are related to treatment outcome. We defined the maximal growth rate period as an age between 12 and 14 for girls and between 13 and 15 for boys. Accordingly, we subdivided patients into 3 groups and analyzed for clinical characteristics and metastasis-free survival (MFS). Most of the clinical characteristics showed no difference among the 3 groups. After a median follow-up of 54 months (range: 6 to 153 mo), the 5-year MFS of the entire cohort was 67.5%+/-3.1%. Patients in the period of maximal growth rate did worst (57.0%+/-5.6%, P=0.02), whereas patients before and after the period of maximal growth rate fared better (77.0%+/-5.1% and 69.4%+/-4.9%, respectively). On multivariate analysis, disease occurrence in the period of maximal growth rate [relative risk (RR) 2.44; 95% confidence interval (CI) 1.37-4.38; P=0.003], American Joint Committee on Cancer stage IIB disease (RR 2.49; 95% CI 1.49-4.17; P=0.001), and a poor histologic response (RR 2.91; 95% CI 1.78-4.77; P<0.001) independently shortened the MFS. The growth characteristics of patients that are available at the time of diagnosis carry prognostic significance and these could be used as a base to design risk-adapted therapy for osteosarcoma.

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., ((Copyright) 2008 Wiley-Liss, Inc.)

Background: 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., Methods: 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., Results: 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 %., Conclusion: 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.

Background: We examined the survivorship and functional outcome of the pasteurized autograft-prosthesis composite for distal femoral osteosarcoma. We also evaluated complications including nonunion, loosening, bony resorption, infection, and fracture., Methods: We retrospectively reviewed 15 distal femoral osteosarcoma patients who underwent reconstructions using pasteurized autograft-prosthesis composite between 1993 and 2003., Results: No patient required graft removal during a minimum follow-up of 35 months (average 56 months; range 35-78 months). The average Musculoskeletal Tumor Society System (MTSS) functional score was 86%. Nonunion developed in five patients, and three of them subsequently showed loosening of the stem. No patient experienced infection or fracture., Conclusions: Our data suggest that the pasteurized autograft-prosthesis composite could be an easily accessible alternative for the reconstruction of large skeletal defects in the distal femur because of the satisfactory functional outcome with a low rate of ultimate failure and complications in this study.

Although several clinicopathologic parameters may be related to metastasis-free survival in osteosarcoma, the importance of prognostic factors with time is largely unknown. Therefore, we asked whether the clinical characteristics of patients with osteosarcoma with metastasis after 2 years differed from those of patients with an earlier metastatic event. We retrospectively reviewed 420 patients with Stage IIB osteosarcoma treated with surgery and chemotherapy. The minimum followup was 3 months (mean, 71.4 months; range, 3-257 months). Among the 420 patients, 167 patients had a metastatic event. A large proportion (43%) of the 35 good responders showed metastasis after 2 years, whereas 24% of the 96 poor responders showed late metastasis. Histologic response and chondroblastic subtype showed time-related changes. Poor histologic response showed a gradual decline in prognostic value and lost its importance after 2 years. Most metastatic events occurred within 2 years after diagnosis; therefore, we recommend new predictive strategies and followup protocol for patients experiencing late relapse.

Ezrin, a cytoskeleton linker protein, has been reported to be involved in the metastasis of solid tumors in animal models and patients in small clinical studies. We analyzed the relationship between immunohistochemical expression of ezrin and the prognosis of osteosarcoma. We retrospectively identified 64 patients with Stage IIB osteosarcomas between 1995 and 2000. Tissue microarrays were constructed from incisional biopsy specimens and immunohistochemical staining was performed. Ezrin expression and other clinicopathologic variables such as age, gender, pathologic subtype, tumor size and location, and histologic response were compared with outcomes. The minimum followup was 12 months (mean, 78.2 months; range, 12-137 months). Twenty-three of 64 patients (35.9%) showed late distant metastasis; 33 of 64 patients (51.6%) showed expression of ezrin, and of these 33 patients, 22 (66.7%) had distant metastasis develop. Multivariate analysis revealed histologic response to preoperative chemotherapy and expression of ezrin predicted disease-free survival. Expression of ezrin in osteosarcoma biopsy specimens is promising as a marker to predict outcome in patients with osteosarcoma.

Primary total femoral resection and reconstruction rarely are indicated for patients with osteosarcoma. We determined the survivorship, complications, and functional outcome of patients with osteosarcomas who had total femoral resections. We evaluated 13 patients with osteosarcomas whose surgical conditions included multiple skip lesions along the femur (Group I, two patients), extensive femoral involvement without interruption (Group II, eight patients), and iatrogenic contamination of the femur secondary to an internal fixation (Group III, three patients). We analyzed the event-free survival, complications, and functional outcome and looked for obvious differences among the three groups. The minimum followup was 9 months (mean, 41 months; range, 9-125 months). The Kaplan-Meier event-free survival rate at 10 years was 34.6% (95% confidence interval, 7.5%-61.7%). All five patients in Groups I and III died. Four of eight patients in Group II were event-free survivors. Four patients had major complications. Five patients had good functional scores. The subset of patients who had relatively small tumors with wide resection margins had a good prognosis. In patients with other clinical conditions, hip disarticulation can be considered.

Among the 665 patients who registered at our hospital, we reviewed 39 cases of high grade primary osteosarcoma in patients who were older than 40 yr of age. The aim of this study was to determine if a primary osteosarcoma in older patients has different clinical features, and a poorer prognosis than in younger patients. Two evaluations were performed. In the first, an attempt was made to determine the possible prognostic factors such as gender, location, size, alkaline phosphatase, radiological findings, chemotherapy intensity, chemotherapy-induced tumor necrosis, and surgical margin. The second evaluation involved assessment of whether there were any significant clinical differences between older patients and adolescents. According to the results, a primary osteosarcoma in older patients did not reveal any significant prognostic variables. A primary osteosarcoma in older patients showed a poorer prognosis due to relatively unusual locations, common abnormal radiological findings, and a poor response to chemotherapy. Therefore, careful attention should be paid to making an accurate diagnosis and new strategies for more effective treatment, including chemotherapy, must to be developed in order to achieve long term survival in older patients with osteosarcoma.

Background: The clinical efficacy of chemotherapy is strongly correlated with the histoculture drug response assay (HDRA) in various types of cancers. However, there have been no previous reports on its use in osteosarcoma., Materials and Methods: Thirty-six fresh samples of human osteosarcoma were evaluated by the HDRA method in order to determine its possible usefulness in the treatment of this cancer. All the materials were obtained either during biopsy or surgical excision at our hospital, between January 2003 and October 2005., Results: A significant inhibition rate in primary biopsies was observed with Adriamycin (ADM) (47.3+/-15.3%); Cisplatin (CDDP) (36.3+/-22.3%); and Carboplatin (CBP) (50.5+/-23.3%); treatment. ADM and CBP demonstrated a statistically significant increase in inhibition rates compared to the other drugs., Conclusion: Even though the HDRA method has many limitations, it might be a feasible and useful technique for selecting and predicting the efficacy of anticancer drugs for osteosarcoma patients.

We compared the accuracy of prediction of the response to neoadjuvant chemotherapy (NAC) in osteosarcoma patients between machine learning approaches of whole tumor utilizing fluorine−18fluorodeoxyglucose (18F-FDG) uptake heterogeneity features and a convolutional neural network of the intratumor image region. In 105 patients with osteosarcoma, 18F-FDG positron emission tomography/computed tomography (PET/CT) images were acquired before (baseline PET0) and after NAC (PET1). Patients were divided into responders and non-responders about neoadjuvant chemotherapy. Quantitative 18F-FDG heterogeneity features were calculated using LIFEX version 4.0. Receiver operating characteristic (ROC) curve analysis of 18F-FDG uptake heterogeneity features was used to predict the response to NAC. Machine learning algorithms and 2-dimensional convolutional neural network (2D CNN) deep learning networks were estimated for predicting NAC response with the baseline PET0 images of the 105 patients. ML was performed using the entire tumor image. The accuracy of the 2D CNN prediction model was evaluated using total tumor slices, the center 20 slices, the center 10 slices, and center slice. A total number of 80 patients was used for k-fold validation by five groups with 16 patients. The CNN network test accuracy estimation was performed using 25 patients. The areas under the ROC curves (AUCs) for baseline PET maximum standardized uptake value (SUVmax), total lesion glycolysis (TLG), metabolic tumor volume (MTV), and gray level size zone matrix (GLSZM) were 0.532, 0.507, 0.510, and 0.626, respectively. The texture features test accuracy of machine learning by random forest and support vector machine were 0.55 and 0. 54, respectively. The k-fold validation accuracy and validation accuracy were 0.968 ± 0.01 and 0.610 ± 0.04, respectively. The test accuracy of total tumor slices, the center 20 slices, center 10 slices, and center slices were 0.625, 0.616, 0.628, and 0.760, respectively. The prediction model for NAC response with baseline PET0 texture features machine learning estimated a poor outcome, but the 2D CNN network using 18F-FDG baseline PET0 images could predict the treatment response before prior chemotherapy in osteosarcoma. Additionally, using the 2D CNN prediction model using a tumor center slice of 18F-FDG PET images before NAC can help decide whether to perform NAC to treat osteosarcoma patients. [ABSTRACT FROM AUTHOR]