Japanese Journal of Clinical Oncology Advance Access originally published online on June 12, 2009
Japanese Journal of Clinical Oncology 2009 39(8):514-522; doi:10.1093/jjco/hyp057
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© The Author (2009). Published by Oxford University Press. All rights reserved
Primary Osteogenic Sarcoma with Pulmonary Metastasis: Clinical Results and Prognostic Factors in 91 Patients
1 Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital
2 Department of Surgery, School of Medicine, National Yang-Ming University, Taipei, Taiwan
For reprints and all correspondence: Wei Ming Chen, Orthopaedic Department, Taipei Veterans General Hospital, 201, Sec. 2, Shih-Pai Road, Taipei 112, Taiwan. E-mail: wmchen{at}vghtpe.gov.tw
Received March 23, 2009; accepted May 3, 2009
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Objective: Osteosarcoma is the most common primary malignant bone tumor. The long-term outcome is poor for patients with metastatic disease.
Methods: From June 1989 to January 2008, 202 patients (128 males and 74 females) with high-grade osteosarcoma of the extremities were treated at our institution. Patients were divided into three groups depending on the time of identification of pulmonary metastasis: group A, identified with primary tumor diagnosis; group B, during whole treatment course; and group C, after completion of treatment. Long-term survival was calculated and factors related to metastases were analyzed.
Results: Ninety-one patients developed pulmonary metastases; 21 in group A, 18 in group B and 52 in group C. The mean period from initial diagnosis to lung metastases in groups B and C was 22.2 months (±20.6). Five-year survival rates were 82.0% and 38.3% in the non-metastasis group and metastasis group, respectively (P < 0.001). The 5-year survival rate was significantly worse in group A than in group B or C (0%, 7.4%, 59.5%, P < 0.001), in patient with more than one lobe involved (27.0%, P = 0.006) and more than three pulmonary nodule metastases (21.3%, P = 0.002). Factors related to the pulmonary metastasis were: old age (65.5% in older than 27.5 years old and 41.6% in younger, P = 0.017), large tumor volume (54.4% in larger than 202.5 ml and 33.7% in smaller, P = 0.005) and elevated lactodehydrogenase (LDH; 55.1% vs.31.0% in normal, P = 0.001).
Conclusions: The prognosis of osteosarcoma with pulmonary metastases is dismal, especially for patients who have primary pulmonary metastases, more than three pulmonary metastatic nodules or involvement of more than one lobe. Factors such as older age, larger tumor volume and elevated LDH may reflect high metastatic rate.
Key Words: osteosarcoma • neoplasm metastasis • survival rate
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Osteosarcoma is the most common primary malignant bone tumor. The long-term outcome is poor for patients with metastatic disease. The lung is the most common target for osteosarcoma metastasis (1). It has been reported that 11–20% of patients have pulmonary metastases at their initial diagnosis, and about half develop lung disease later (2–4). However, during the past decade, thanks to the intensive regimens of multi-agent chemotherapy, aggressive surgical techniques and advanced diagnostic equipment, the long-term survival rate for osteosarcoma patients has dramatically improved. However, despite the encouraging trend to longer survival, many patients still face a dismal outcome. Numerous articles have reported factors that can be linked to poor outcome, such as elevated serum alkaline phosphatase (SAP) levels (5–7), large tumor size (8,9) and lower tumor necrosis rate (10,11). However, other studies have produced contradictory results.
The aim of this study was to assess the influence of various patient-, tumor- and treatment-related factors in patients with pulmonary metastases. Our secondary goal was to report demographic data in our country and the long-term outcome of patients treated in our group.
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PATIENTS AND METHODS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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From June 1989 to January 2008, 202 patients with histologically proven osteosarcoma were enrolled in the study. Patients whose osteosarcomas had an axial location, or who had low-grade tumors or who had been treated with surgery at other institutions were excluded from the study. The subjects’ age and sex and tumor-related factors, such as location, volume, histologic subtype, post-chemotherapy necrosis rate and biologic markers, were recorded and analyzed.
Tumor length, width and depth were measured, based upon magnetic resonance imaging scans. Then these parameters were calculated by the ellipsoid formula (V = 4/3
x ABC) (8).
All of the specimens gained by excision biopsy and wide excision during the 19 years were reclassified and the necrosis rates were re-evaluated by an experienced pathologist. The subtypes of osteosarcoma were classified as: osteoblastic, fibroblastic, chondroblastic, telangiectatic and others. Response to pre-operative chemotherapy was assessed according to the scale of Huvos et al. (12), where grade I denotes 0–50% necrosis; grade II, 5–90% necrosis; grade III, 91–99% necrosis; and grade IV, 100% necrosis. A good response was defined as stages III and IV. The necrotic rate could not be evaluated in 48 cases because the specimen slides had faded with age and not enough information remained for accurate calculation.
The pulmonary survey was performed with plain films and chest computed tomographic (CT) scans. CT was scheduled at first diagnosis, before surgery and every 3 months during the first 2 years post- surgery, every 6 months during the third to fifth years and annually in later years. We recorded the metastatic pulmonary lobes and the number of tumor nodules. Patients were divided into three groups depending on the time of identification of pulmonary metastasis: group A, identified with primary tumor diagnosis; group B, identified during whole treatment course (included neoadjuvant chemotherapy, surgery and adjuvant chemotherapy); and group C: identified after completion of treatment (Fig. 1). In addition, the 5-year survival rates were compared.
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The levels of SAP and serum lactodehydrogenase (LDH) were measured at admission (at first diagnosis) and reported as international units (IUs). The normal range for LDH was 95–213 IU/l. And the level of SAP was classified after adjustment for age and gender: 2–10 years 100–350 UI/l; 10–13 years female 110–400 UI/l; 13–15 years male 125–500 UI/l; 20–50 years 25–100 UI/l; and other childhood age 73–300 UI/l. (13).
All patients except four received neoadjuvant chemotherapy. Three of the four underwent direct amputations because the tumor was too large at diagnosis. Another patient immediately underwent surgery and the tumor was excised because the tumor was small (25 cm3) and the osteosarcoma was not the only diagnosis before surgery. Seventeen patients received neoadjuvant chemotherapy elsewhere and were referred to our hospital for tumor excision and post-surgical treatment. However, the records of the chemotherapy protocols of these patients were unclear. Patients who received neoadjuvant chemotherapy at our hospital underwent six types of protocols during the study period (Fig. 2). During the first few years of treatment in this study, there was only a single agent (protocol 1) or two combined regimens (protocols 2 and 3). From June 1993, we started to use three and four combined regimens (protocols 4–6). Ifosfamide (Mitoxana, Meda AB, Solna, Sweden) was added to the regimens in June 1993.
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After receiving neoadjuvant chemotherapy, all patients received wide excisions and initially their limbs were salvaged; in 15 patients, however, the tumor was too large and had invaded the neurovascular system. Initially, the limbs were salvaged, except in 15 patients whose tumors became too large and invaded the neurovascular system. These patients underwent amputations. Additionally, patients with pulmonary metastases received thoracotomy at least once, except those with too many lung lesions to excise or those who were in such poor condition that they could not tolerate the procedure.
Long-term survival was a major focus of this study. The overall survival rate was calculated from the date of diagnostic biopsy until death or last follow-up visit. The survival curves were calculated according to the Kaplan–Meier method and compared by means of the log-rank test. Differences in the demographics and presenting characters between metastatic and non-metastatic disease groups were evaluated by Fisher's exact test or Pearson exact 
2 test. P values <0.05 were considered significant. The cut-off points of patient's age and tumor volume were calculated by receiver operating characteristic curve.
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Patient Demographics
In the group of 202 patients, 128 were males and 74 were females, and the mean age was 20.2 years (range: 5–84 years). The mean follow-up was 58.2 months (range: 2–233 months). Ninety-one patients (45.0%) patients developed pulmonary metastases. Of these patients, there were 62 males and 29 females. The mean age was 22.5 years (range: 5–84 years) and the mean follow-up was 45.7 months (range: 3–218 months).
When age was evaluated, the cut-off point of 27.5 years old was compared. In the older group, 65.5% developed pulmonary metastases and only 41.6% in the younger group. The difference was significant (Table 1). Few patients were older than 40 years; however, 17 patients were older than 40 years and 11 (64.7%) had pulmonary metastases.
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Timing of Metastases
Of the 91 patients with pulmonary metastases, there were 21 patients (23.1%) in group A, 18 (19.8%) in group B and 52 (57.1%) in group C. The mean time span from initial diagnoses to pulmonary metastases was 16.1 months in all patients in the metastatic group; the time span was 22.1 months in patients with metastases later (group B + C) (median: 17.5 months; range: 2–108 months). Gender, age, histology subtype and location in each group were not different (Table 2). The 5-year survival rate was 38.3% in the metastases group and 82.0% in the non-metastases group (P = 0.001) (Fig. 3). As for the timing of metastases, the 5-year survival rate was 0% in the primary metastases group (group A), 7.4% in group B and 59.5% in group C. Patients with earlier pulmonary metastases had a significantly poor prognosis than did those with later pulmonary metastases (P < 0.001) (Fig. 3).
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Tumor Volume
Information on tumor size was available for 182 primary tumors. The median volume was 198.5 ml (range: 25.0–4875.2 mL), and the mean volume was 344.3 ml (±547.0 ml). The mean tumor volume increased to 382.6 ml in patients with pulmonary metastases and to 645.2 ml in patients with primary pulmonary metastases (group A). Eleven patients had extremely large tumors (>1000 ml). Of these patients, 5 (45.5%) developed primary pulmonary metastatic disease and one developed lung disease during neoadjuvant chemotherapy (group B). Nine of these 11 patients had died by the time of the last follow-up visit. While 202.5 ml was established as a cut-off point of tumor size, the ratio of lung metastasis was 54.4% in larger tumors and 33.7% in smaller tumors (P = 0.005). And, the ratio of primary lung metastasis was 16.7% and 6.5% in the larger and smaller groups, respectively P = 0.032) (Table 1). As for the long-term outcome, the 5-year survival rate was poorer in metastatic patients with larger tumors (30.9% vs. 45.5%, P = 0.03, cut-off point = 264.0 ml) (Table 3).
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Tumor Location
The most common location for the primary tumor was the distal femur (n = 94, 46.5%). The proximal tibia (n = 57, 28.2%) and proximal humerus (n = 17, 8.4%) were the next most common sites. Tumor location was not related to lung metastasis (P = 0.793) (Table 1).
Histology
The most common histologic type was the osteoblastic type (n = 101, 50.0%), followed by the chondroblastic type (n = 24, 11.9%) and the fibroblastic type (n = 23, 11.4%). The histologic subtypes of osteosarcoma in patient with metastases were: osteoblastic, 56.0%; chondroblastic, 13.2%; and fibroblastic, 11.0%. There was no difference in the distribution of subtypes between patients with or without pulmonary metastases (P = 0.829) (Table 1). As for the long-term outcome, there was no statistical difference between these groups (P = 0.646) (Table 3).
Biochemical Markers
Of the patients with known LDH and SAP levels at diagnosis, 58.4% had elevated serum LDH levels and 75.7% had elevated SAP levels. When patients were compared by LDH levels, the lung metastasis rate was 55.1% and the primary lung metastasis rate was 15.3% in the elevated group. These results were significantly higher than among those with normal serum LDH levels (P = 0.001 and 0.007) (Table 1). When we evaluated the SAP levels, the primary metastasis rate was higher in the group with elevated levels than in that with normal levels (13.7% vs. 0.0%, P = 0.006) (Table 1). Among patients with lung metastasis, poorer survival was noted in the group with elevated alkaline phosphatase levels (5-year survival rate: 68.4% vs. 30.0%; P = 0.005) (Table 3). This pattern was not seen among the patients with elevated LDH levels.
Nodules and Lobes of Pulmonary Metastases
Of the patients with pulmonary metastases, 69.2% had involvement of more than one lobe and 54.9% had involvement of more than three tumor nodules. Among patients with primary pulmonary metastases (group A), 95.2% of the patients had more than three tumor nodules and 85.7% had more than one lobe involved. The ratios were higher than in groups B and C (P < 0.001 and 0.022) (Table 2). The 5-year survival rate was poorer among patients who had more than three tumor nodules (P = 0.002) and tumor invasion of more than one lobe (P = 0.006), compared with those who had involvement of fewer lobes (Table 3). Of the groups B and C, the number of tumor nodules and the degree of lobes involvement were not related to initial treatment of primary tumor (the neoadjuvant chemotherapy regimen and the surgery type).
Chemotherapy
Before February 1996, 19 patients with pulmonary metastases underwent single or two courses of combined neoadjuvant chemotherapy regimen. The 5-year survival rate among these patients was only 20.7%. After July 1993 and October 1995, three and four combined neoadjuvant chemotherapy regimens were enrolled in our protocols. Of these patients, the 5-year survival rate was elevated (46.6%) but did not reach statistical significance (P = 0.08) (Table 3). After ifosfamide was added to our protocols in June 1993, the 5-year survival rate rose from 14.3% to 53.6%, which was statistically significant (Table 3). When a patient was not found to have pulmonary metastases at the initial diagnosis, the secondary metastases rate was not related to the chemotherapy protocols.
Histologic Response to Neoadjuvant Chemotherapy
Among the 154 patients, 81 (52.6%) had good responses and 73 (47.7%) had poor responses to neoadjuvant chemotherapy. We also calculated the good response rate for patients with metastases (46.3%) and primary metastases (47.1%). No relationship between metastasis and histologic response was found (P = 0.167) (Table 1). In patients with pulmonary metastases, the 5-year survival rate was 36.8% in patients with a good response and 37.0% in patients with a poor one. The tumor necrosis rate after neoadjuvant chemotherapy was not related to long-term survival in our study.
Thoracotomy
Of the patient with pulmonary metastases, 52 patients (57.1%) received at least one thoracotomy. One patient had primary pulmonary metastases and underwent thoracotomy eight times, but finally died after 60 months of follow-up. Two patients did not undergo thoracotomy because their lung tumors disappeared after chemotherapy. Another 37 patients did not undergo thoracotomy due to their poor medical condition or due to the presence of too many lung nodules, or resolution of nodules during chemotherapy. The 5-year survival rate of patients who underwent thoracotomy was 45.6%, compared with 28.3% among those who did not undergo the procedure. This was not statistically significant (P = 0.069) (Table 3).
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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The lung is the most common site for the development of metastases in patients with osteosarcoma (1). It has been reported that
50% of the patients are found to have metastatic disease at the initial consultation or at follow-up. Furthermore, 11–20% of the patients are found to have primary pulmonary metastases (2–4). In the current study, the ratio of pulmonary metastatic osteosarcomas was similar to that reported in other studies (45.0%). Long-term follow-up revealed that the metastatic rate was from 10% to 40%. The outcome was poor compared with the outcome of patients with localized disease (60–80%) (11,14–18). On the positive side, patient outcome had significantly improved over the period of the study: 25 years ago, the 5-year survival rate was only 2% (19). The dramatic advancement could be attributed to aggressive multi-agent chemotherapy and surgical approaches that are designed to remove the primary tumor and all the metastatic tumors. As in other reports, the 5-year survival rate fell dramatically, from 82.0% to 38.3%, when a patient developed lung metastases. However, after treatment with intensive chemotherapy, the outcome was much better. Goorin et al. (20) found that the chemotherapy response rate in measurable osteosarcoma is 15% or less for many agents. In the first few years of the group we studied, 19 patients with pulmonary metastases underwent single or two combined regimens neoadjuvant chemotherapy and the long-term outcome was unsatisfactory (5-year survival rate: 20.7%). However, while three or four combined regimens were used during these 10 years, the 5-year survival rate for metastatic osteosarcoma improved, to 46.6%. Even though the difference was statistically insignificant (P = 0.081), we do see a favorable clinical trend from combination therapy.
The importance of ifosfamide while treating osteosarcoma clinically has been reported in many studies (20–22). Duan et al. (23) recently reported that the active metabolite of ifosfamide, 4-hydroperoxycyclophosphamide, could lead to enhanced Fas ligand expression and protein production. It played a very important role in chemotherapy-induced necrosis of tumor cells (24–26). The 5-year survival rate was also dramatically improved, from 14.3% to 53.6%.
The timing of lung metastases was also analyzed. In patients of groups B and C, the median time to first lung metastases was 22.1 months in our study. However, even 9 years later, newly found metastasis was still discovered. So, the current survey for lung disease in our group after surgery (every 3 months in first 2 years, every 6 months during third to fifth years and each year in later years) was quite important. The dismal long-term outcome for primary metastases reported in many studies (4,15,27,28) ranges from 11% to 29%, and 0% in our study. When we compared the outcome of patients depending upon the time they developed lung metastasis, the prognosis was significantly worse in group A (primary metastases), followed by groups B and C (P < 0.001). This may be due to the more aggressive biologic character of the tumor or larger tumor burden in primary pulmonary metastases. However, a different result was reported by Tsuchiya et al. (27), who found that the worst outcome occurred among patients with metastases discovered during pre-operative chemotherapy (5-year survival rate = 0%). The next-worse outcomes occurred when metastases were noted during post-operative chemotherapy (6%), after completion of treatment (31%) and at initial presentation (18%). The difference may be contributed to different chemotherapy protocols or varied schedule for chest survey.
The relationship between tumor necrosis and pulmonary metastases was discussed in some studies. Bacci et al. (10) declared that the rate of complete response was 21% in patients with localized tumor and 0% in patients with metastatic disease. However, while tumor response was defined as a good or poor response, the good response rate in patients with primary metastases was very similar to that of patients with localized disease. Many studies have reported that tumor necrosis is a major factor related to the outcome of the osteosarcoma. Meyers et al. (11) also noted that in patients with pulmonary metastases, the long-term survival rate was also related to the necrosis rate. A contrary result was reported by Mialou et al. (5). These researchers reported a study of 77 patients with primary pulmonary metastases, in whom the 5-year survival rate was not statistically different for good and poor responders. We agree with this result. In our study, the long-term outcome was poor for pulmonary metastases, even in good or poor responders.
When Nachman et al. (29) evaluated the tumor necrosis rate (primary and metastatic tumor cell) in patients with primary pulmonary metastases after neoadjuvant chemotherapy, they concluded that there were heterogeneity and different chemosensitivities between the cells. Therefore, the localized tumor necrosis cannot be a standard for all of the tumors cells.
In the studies of Bieling et al. (8) and Kaste et al. (9), it was found that the tumor volume was not only a significant predictor of pulmonary metastases but also a predicted poor long-term survival. These findings were also observed in our study. However, we also found that as the tumor size increased, metastasis developed earlier (mean volume: 344.3 ml in metastatic osteosarcoma and 382.6 ml in primary metastatic osteosarcoma). This may be due to the fact that the larger tumor has an increased venous dissemination and a greater tumor burden.
Extensive tumor invasion of the lung (more than three tumor nodules and more than one lobe involved) was commonly seen in our study. Unfortunately, the dismal outcome was reported in many studies (30–35). With more extensive disease in our study, the 5-year survival rate dropped apparently. This may have been due to the fact that the numerous tumor nodules were difficult to resect completely. Although some authors did not report any such relationship (35–37), different techniques may have been used to evaluate the lungs or studies may have included limited populations.
SAP and LDH levels were the important biologic markers of tumor activity in human and animals with osteosarcoma (34,36). Tomer et al. (37) reported a higher disease-free survival rate with normal SAP levels. The relationship between SAP level and outcome was also reported by Bacci et al. (39) and was evident in our study as well. Bacci et al. reported that the 5-year disease-free survival rate for those with normal SAP levels and those with elevated levels was 67% vs. 54%, respectively (P = 0.001). In our study, the 5-year survival rates for those with normal SAP levels and those with elevated levels were 82.8% vs. 55.3%, respectively (P = 0.001, in all 202 patients). This poor result with elevated SAP levels was also found in patients with pulmonary metastases.
However, this was not the case in patients with pulmonary metastasis. We also found that the LDH level was a factor in primary metastases. Once LDH was elevated, the primary metastases rate increased from 14.3% to 85.7% (P = 0.009). It was also reported by Bacci et al. (38) that elevated LDH levels were noted in 64% of the patients with metastatic disease and in 33% of those with localized disease (P < 0.0001).
The role of resection of the pulmonary nodules has been extensively studied (10,14,27,30,31). Bacci et al. (10) reported 23 patients with chemotherapy followed by simultaneous resection of primary and metastatic lesion. Patients with non-resectable metastases (four patients) and incomplete resection of pulmonary nodules (one patient) died of tumors between 13 and 28 months. Even with the usually poor outcome of metastatic osteosarcoma, in our study, the 5-year survival rate increased from 28.3% to 45.6% after at least one thoracotomy. Although it did not reach statistical significance (P = 0.069), we still suggest surgical removal of all the metastatic tumors. We suggest doing so even twice or more times, if the patient can tolerate it.
Today, even with improved treatment, the long-term survival rate of metastatic osteosarcoma is unsatisfactory. Once high-risk metastatic factors are noted, such as older age, large tumor size and elevated LDH level, we should pay more attention to evaluating the possibility of metastasis to the lung. Besides, more efforts should be made to improve survival by identifying innovative therapeutic approaches, such as novel chemotherapy, gene therapy, stereotactic radiotherapy and immunotherapy.
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Conflict of interest statement |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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None declared.
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References |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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