Biomedical subjects
Publications and source records attributed to John H Healey.
Leydig cell tumors account for 3% of testicular tumors and have never been reported after treatment for Ewing's sarcoma. We report the unusual occurrence of a patient who developed a Leydig cell tumor of the testis 18 years after successful treatment for Ewing's sarcoma. Additional monitoring for second malignancies may become appropriate as long-term survival continues to improve for patients with Ewing's sarcoma.
BACKGROUND: Local recurrence in osteosarcoma is clinically distinct from metastasis, although associated with a similar reduction in survival. The prognostic factors in locally recurrent osteosarcoma were investigated and these factors were translated into a management strategy. METHODS: In all, 407 consecutive patients with skeletal osteosarcoma between 1977 and 2002 were analyzed. Twenty-three patients with resectable local recurrence were analyzed. Clinical and tumor-related factors were assessed for significance in relation to survival and a management strategy was formulated based on factors found to be independently significant for survival. RESULTS: Seventeen of the 23 patients underwent primary resections and initial treatment, yielding an overall local recurrence rate of 4.2% for resectable cancer. Median time to local recurrence was 13 months (95% confidence interval, 9-16 months). The 5-year and 10-year survival rates in the recurrent cases were 29% and 10%, respectively. All patients received chemotherapy both for their primary and recurrent disease. Increased risk of local recurrence (P < .0001) was strongly correlated with positive margins of resection. The rate of local recurrence was not related to chemotherapy-associated necrosis in the primary tumor. Nevertheless, neoadjuvant therapy halved the risk of local recurrence (odds ratio, 1.92; P = .3, power 10%). The strongest correlate with poor survival was local recurrence within the first year after primary resection (P = .001), followed by metastasis at the time of first local recurrence (P = .04) and failure to achieve clinical remission after disease recurrence (P = .04). Chemotherapy-associated necrosis and margins of resection of the primary tumor were not significant prognostic variables for survival. Survival differed significantly among patients defined by local disease-free interval and lung metastasis (P = .0001). They required an individualized approach as captured in the management algorithm. CONCLUSION: There is a residual risk of local recurrence in patients despite favorable chemotherapy-associated necrosis and negative margins of resection. A treatment strategy emphasizing clinical remission at all identifiable sites offers the highest likelihood of survival in this patient population.
PURPOSE: To evaluate local control and toxicity for very young children treated with multimodality therapy for rhabdomyosarcoma (RMS). METHODS AND MATERIALS: From 1990 to 2004, 20 patients or=1 year after diagnosis (15) in terms of mild, moderate, or severe deficits. RESULTS: Median follow-up was 33 months for survivors and 23 months for all patients. Two-year actuarial local control, event-free survival, disease-specific survival, and overall survival were 84%, 52%, 74%, and 62%, respectively. All patients who began EBRT<or=18 weeks after the start of CMT had their disease controlled locally. Five have mild deficits and 10 have no deficits. CONCLUSIONS: A reduced dose of 36-Gy EBRT after delayed GTR may maximize local control while minimizing long-term sequelae for very young children with RMS, but unresectable tumors (e.g., parameningeal) require higher doses. Normal-tissue-sparing techniques such as intensity-modulated radiation therapy and IOHDR are encouraged. Local control may be maximized when EBRT begins <or=18 weeks after initiation of CMT, but further study is warranted. Longer follow-up is required to determine the full extent of late effects.
PURPOSE: Composite sacropelvic resection for locally advanced recurrent rectal cancer is a high-risk procedure that benefits select patients. We reviewed our recent institutional experience to evaluate case selection, morbidity, and outcomes. METHODS: Between 1987 and 2004, 29 patients underwent composite resection for recurrent locoregional rectal cancer (17 females; median age, 60 years). Clinicopathologic indicators were evaluated as indicators of survival by log-rank test and Cox proportional hazards model. RESULTS: Of 29 total patients, 27 (93 percent) received radiotherapy with their previous surgery (n = 10; 34 percent) or before sacrectomy (n = 17; 59 percent), and 12 (41 percent) received intraoperative therapy. Sacral resections were performed at S2/S3 (55 percent) or S4/S5 (45 percent) using anterior (41 percent) or combined anterior-posterior approach (59 percent), with adherence to (62 percent) or cortical invasion in (38 percent) the sacrum. A majority of those who had undergone previous abdominoperineal resection had total exenteration (9/13), whereas most patients who had undergone a previous sphincter-preserving procedure had abdominoperineal resection (12/16) and none had exenteration. Pedicle flaps (omental, 11; abdominal rectus, 7) often were used. A median of five (range, 1-33) units of blood was given intraoperatively. Transfusions were associated with previous abdominoperineal resection (P < 0.03), correlating strongly with postoperative morbidity (P < 0.02). There were 33 complications in 17 (59 percent) patients, most commonly perineal wound breakdown (9 (31 percent)) and pelvic abscess (5 (17 percent)). Median hospital stay was 18 (range, 7-56) days, significantly longer in patients with previous abdominoperineal resection (P < 0.02) or postoperative morbidity (P < 0.03). The only postoperative death was from pelvic sepsis. Resection was complete (R0) in 18 patients (62 percent), with microscopically positive margins (R1) in 10 (34 percent) and grossly positive margins (R2) in 1 (3 percent). Two-year and five-year recurrence rates were 47 and 85 percent, respectively; disease-specific survival was 63 and 20 percent, respectively. Less transfusion (P = 0.03), R0 resection (P = 0.005), lack of anterior organ involvement (P = 0.02), and absence of cortical bone invasion (P < 0.001) were associated with better survival on univariate analysis; original colorectal cancer stage was not. CONCLUSIONS: Sacrectomy for rectal cancer is a high-risk procedure that can achieve clear resection margins with low mortality in select patients. This procedure has a low cure rate but may provide local disease control with acceptable morbidity.
A device is presented that positions ultrahigh molecular weight polyethylene (UHMWPE) debris against periprosthetic bone surfaces. This can facilitate the study of aseptic loosening associated with cemented joint prostheses by speeding the appearance of this debris within the periprosthetic space. The device, composed of a 100 microm thick bioabsorbable membrane impregnated with 1.4 x 10(9) sub-micron particles of UHMWPE debris, is positioned on the endosteum of the bone prior to the insertion of the cemented orthopedic implant. An in vitro pullout study and an in vivo canine pilot study were performed to investigate its potential to accelerate "time to aseptic loosening" of cemented prosthetic joints. Pullout studies characterized the influence of the membrane on initial implant fixation. The tensile stresses (mean+/-std.dev.) required to withdraw a prosthesis cemented into canine femurs with and without the membrane were 1.15+/-0.3 and 1.54+/-0.01 MPa, respectively; these findings were not significantly different (p > 0.4). The in vivo pilot study, involving five dogs, was performed to evaluate the efficacy of the debris to accelerate loosening in a canine cemented hip arthroplasty. Aseptic loosening and lameness occurred within 12 months, quicker than the 30 months reported in a retrospective clinical review of canine hip arthroplasty.
UNLABELLED: Myxofibrosarcoma (MFS) has a high local failure rate of up to 79%. We conducted a retrospective analysis on all patients with the diagnosis of myxofibrosarcoma seen between 1990 and 2004 to assess whether improved imaging with MRI reduced local recurrence, increased survival, and whether radiotherapy following resection influenced outcome. Twenty-one patients were treated for MFS with a median followup of 52 months (range, 18-122). All patients were surgically treated, with 19 receiving limb-sparing surgery. All patients with high grade disease, positive margins, or a pre-referral procedure received radiation therapy. The local recurrence rate was 57% for patients with a prior outside procedure (8 of 14), while patients with no prior surgery had a rate of 14% (1 of 7). Prior marginal excision and diffuse fascial spread on MRI predicted an increased local recurrence rate. The disease-free survival at 5 years was 43% (SE, 22%) for low-grade disease and 39% (SE, 18%) for high- grade disease. Magnetic resonance imaging observations suggest a unique pattern of diffuse spread along fascial planes that could be responsible for the high local recurrence. Radiation did not compensate for positive margins, nor did it reduce recurrence after negative margins. LEVEL OF EVIDENCE: Therapeutic study, level IV (case series).
Advocates of scapular replacement suggest sparing the deltoid should be a prerequisite for use of a scapular prosthesis. We evaluated the importance of a functioning deltoid in scapular replacement for malignant tumors. We retrospectively reviewed 19 patients who received scapular prostheses after resection of a malignant tumor. The median followup was 18 months (range, 12-124 months). The axillary nerve was resected in eight patients and spared in 11 patients. The average International Society of Limb Salvage score was 25 of 30 points (range, 21-27 points). The average scores for patients with and without axillary nerve resection were 24 points (range, 21-25 points) and 26 points (range, 23-27 points), respectively. There was a difference between the two groups in hand positioning, overall function, and pain. However, there were no differences in emotional acceptance, lifting ability, or hand dexterity. We favor using a scapular prosthesis if there is a functioning deltoid; however resection of the deltoid should not be considered an absolute contraindication for scapular replacement.
UNLABELLED: Periprosthetic infections of oncologic reconstructions have an amputation rate between 37% and 87%. Eleven patients with an infected knee reconstruction following limb salvage surgery for cancer were treated with the staged protocol. All patients underwent prosthetic removal and implantation of an antibiotic-impregnated cement spacer, i.v. antibiotic therapy, repeat debridement and spacer change, and delayed prosthetic reconstruction and free tissue transfer. At the time of reconstruction, the median bone defect was 185 mm. The mean soft tissue defect was 112 cm2. Coverage was obtained with a free musculocutaneous flap. All limbs were spared without amputation or flap loss. The mean functional outcome as measured by the Musculoskeletal Tumor Society lower extremity score was 23 of 30. Infections of large prosthetic reconstructions about the knee can be salvaged successfully with repetitive debridement, staged prosthetic reimplantation, and free tissue transfer. Free tissue transfer improves the soft tissue envelope and allows restoration of joint motion. LEVEL OF EVIDENCE: Case Series. Level IV.
BACKGROUND: Patients with cancer who undergo surgery about the hip are at increased risk for the development of deep vein thrombosis. We implemented a program of chemical and mechanical prophylaxis to prevent this problem. This study was performed to assess the effectiveness of that program. METHODS: Eighty-seven consecutive patients with an active malignant tumor who underwent hip replacement surgery at our institution over a two-year period were included in the study. All patients were treated with intermittent pneumatic compression devices. Seventy-eight patients received anticoagulants, and nine did not. Postoperative surveillance for proximal deep vein thrombosis was routinely performed on all patients with duplex Doppler ultrasonography. RESULTS: Four patients had proximal deep vein thrombosis, and one patient, who did not receive anticoagulation, had a nonfatal pulmonary embolism. The use of prophylactic low-molecular-weight heparin (dalteparin) was associated with a 4% rate of proximal deep vein thrombosis (three of seventy-eight patients). Proximal deep vein thrombosis developed in three of eight patients with pelvic disease, one of nineteen patients with femoral disease, and zero of sixty patients with hip disease (p < 0.00001). The prevalence of proximal deep vein thrombosis was significantly higher (p < 0.02) following replacements in patients with sarcoma (three of twenty-one) than it was after replacements in patients with carcinoma (zero of fifty-seven) or hematologic malignant disease (one of nine). On multivariate analysis, only the location of the disease (the pelvis, femur, or hip) was found to be independently significant for an association with deep vein thrombosis. A wound complication developed in four of twenty-one patients with sarcoma and no patient with carcinoma or hematologic malignant disease (p < 0.001). The pathologic type was the only factor studied that was independently significant for an association with wound complications on multivariate analysis. CONCLUSIONS: The rate of proximal deep vein thrombosis in patients who had undergone hip replacement for oncologic indications was low when the use of an intermittent pneumatic compression device was supplemented with prophylaxis with low-molecular-weight heparin.
BACKGROUND: Patellar complications following endoprosthetic reconstruction can occur as a result of anatomic, physiologic, and surgical reasons. Patellar impingement on tibial polyethylene is a complication of distal femoral replacement, and it is frequently related to inaccurate restoration of the joint line and to soft-tissue contracture. The purpose of our study was to determine the prevalence and type of patellar complications following distal femoral replacements after excisions of bone tumors. METHODS: The results of reconstruction with use of a rotating-hinge endoprosthesis following excision of a distal femoral tumor in forty-three patients were retrospectively reviewed. Patients were followed clinically and radiographically for a minimum of forty-eight months or until death. Pain status, functional scores, and the range of motion were determined from a prospectively maintained database. The ratio of the patellar tendon length to the height of the patellar tendon insertion, as described by Insall and Salvati, was calculated. In addition, we attempted to determine whether the position of the patella was associated with anterior knee pain or with the functional scores derived with use of the International Society of Limb Salvage (ISOLS) scoring system. RESULTS: Thirty-five patellar complications, including eleven cases of impingement, occurred in twenty-seven patients (63%). We found no difference, on the basis of our sample size, with regard to the presence of patellar pain, the range of motion, or the Insall-Salvati ratio between the patients with and those without impingement. The ratio of the patellar tendon length to the height of the patellar tendon insertion averaged 0.9 in the group with impingement and 1.4 in the group without impingement (p = 0.07). The ISOLS score averaged 21.2 points in the group with impingement compared with 24.2 points in the group without impingement (p = 0.01). Patella baja occurred in nine patients. The average ISOLS score (and standard deviation) was 20.1 +/- 4.4 points for the patients with patella baja compared with 24.8 +/- 3.9 points in the group with a normal patellar position (p = 0.004). Patellar fracture occurred in two patients, and osteonecrosis occurred in two patients. These patients were treated nonoperatively. CONCLUSIONS: Patellar complications are common after distal femoral resection and endoprosthetic reconstruction. Patellar impingement on the polyethylene tibial bearing surface is a more common and important complication of distal femoral replacement than has been reported to date. Patella baja is also a relatively common complication, which has a negative impact on knee function.
Pigmented villonodular synovitis is a proliferative condition of the synovium. Monoarticular involvement, the most common process, occurs in two forms: localized and diffuse. The localized form is characterized by focal involvement of the synovium, with either nodular or pedunculated masses; the diffuse form affects virtually the entire synovium. The localized form has an excellent prognosis and a low recurrence rate when managed surgically. The more common diffuse form has a reported recurrence rate of up to 46%. Although the condition can present in any joint, the knee is the most commonly affected site. Pigmented villonodular synovitis is often aggressive, with marked extra-articular extension. Open synovectomy is the standard method of management. Arthroscopic synovectomy, which has gained popularity, has several advantages over the open technique, but it is associated with higher recurrence rates in diffuse pigmented villonodular synovitis. Synovectomy by any approach, however, may prevent secondary osteoarthritis and subsequent joint arthroplasty. Radiation-induced synovectomy has shown mixed results. Combined surgical and nonsurgical approaches may be necessary, and in some patients, total joint arthroplasty may be the only effective treatment.
BACKGROUND: Overall survival after recurrence of osteosarcoma (OS) is < 30%. The authors reported their experience treating recurrent OS at the time of first recurrence (R1). METHODS: Patients with high-grade OS who achieved complete disease remission (CR) after primary surgery and chemotherapy, and patients who were treated at R1 at Memorial Sloan-Kettering Cancer Center (New York, NY) after 1990 were analyzed by retrospective chart review. RESULTS: For 43 eligible patients, the median time to R1 from initial diagnosis was 21.7 months (range, 4.6-135.7 mos). The lungs were the most common sites of disease recurrence (n = 33 of 43). With a median follow-up of 15.2 months (range, 0.7-158.3 mos) after R1, 15 of 43 (35%) patients were alive. Four of 43 patients were treated with surgery alone (3 patients were alive and 1 had died of progressive disease at the time of last follow-up). Due to unresectable disease, eight patients received only chemotherapy, none of whom survived. For patients with disease recurrence treated with chemotherapy and surgery (n = 31), 22 patients achieved a second CR (CR2). Nine patients were alive and in disease remission (29%) at the time of last follow-up. Twenty-three patients received ifosfamide as part of their retrieval regimen. Of the 18 who achieved a CR2, 8 experienced disease recurrence, 7 remain alive in CR2, and 3 died due to toxicity. Eight patients did not receive ifosfamide. Of these, 4 achieved a CR2 but 3 subsequently experienced disease recurrence. CONCLUSIONS: At R1, 22 of 31 patients achieved a CR2 with aggressive surgery and chemotherapy. The majority of these patients subsequently developed a disease recurrence. Patients appeared to benefit from the addition of ifosfamide to their retrieval regimens. In the end, the role of chemotherapy in recurrent OS continues to remain undefined.
PURPOSE: To evaluate the outcomes of patients with Ewing's sarcoma family of tumors (ESFT) treated with modern radiotherapy techniques with MRI along with optimal chemotherapy. METHODS AND MATERIALS: The records of all 60 patients with ESFT who received radiation to the primary site between 1990 and 2004 were reviewed. All patients received chemotherapy, including vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide. Radiation was used as the sole modality for local control in 31 patients and was given either before (n=3) or after surgical resection (n=26) in the remainder. All patients had MRI and CT scan-based treatment planning, and 43% received intensity-modulated radiation therapy. Radiation doses ranged from 30 Gy to 60 Gy (median, 51 Gy), and 35% received hyperfractionated radiotherapy. RESULTS: Median age was 16 years (range, 2-40 years). Because of selection bias for radiotherapy, the majority of primary tumors were centrally located (72%): spine (n=18), pelvis (n=15), extremities (n=12), chest wall (n=5), head and neck (n=5), and other (n=5). Thirty-eight percent of patients presented with metastatic disease, and 52% of primary tumors were >or=8 cm. Actuarial 3-year local control was 77%. The presence of metastases at diagnosis was an adverse prognostic factor for local control (84% vs. 61%, p=0.036). No other predictive factors for local failure were identified. In patients without metastatic disease, 3-year disease-free and overall survival rates were 70% and 86%, respectively, whereas in patients with metastases they were both 21%. Follow-up of surviving patients was 6-178 months (median, 41 months). CONCLUSION: In this unfavorable cohort of ESFT patients, radiation therapy was an effective modality for local control, especially for patients without metastases. The presence of metastases at diagnosis is a predictive factor not only for death but also for local failure.
PURPOSE: Life expectancy is routinely used as part of the decision-making process in deciding the value of surgery for the treatment of bone metastases. We sought to investigate the validity of frequently used indices in the prognostication of survival in patients with metastatic bone disease. METHODS: The study prospectively assessed 191 patients who underwent surgery for metastatic bone disease. Diagnostic, staging, nutritional, and hematologic parameters cited to be related to life expectancy were evaluated. Preoperatively, the surgeon recorded an estimate of projected life expectancy for each patient. The time until death was recorded. RESULTS: Kaplan-Meier survival analyses indicated that the survival estimate, primary diagnosis, use of systemic therapy, Eastern Cooperative Oncology Group (ECOG) performance status, number of bone metastases, presence of visceral metastases, and serum hemoglobin, albumin, and lymphocyte counts were significant for predicting survival (P < .004). Cox regression analysis indicated that the independently significant predictors of survival were diagnosis (P < .006), ECOG performance status (P < .04), number of bone metastases (P < .008), presence of visceral metastases (P < .03), hemoglobin count (P < .009), and survival estimate (P < .00005). Diagnosis, ECOG performance status, and visceral metastases covaried with surgeon survival estimate. Linear regression and receiver-operator characteristic assessment confirmed that clinician estimation was the most accurate predictor of survival, followed by hemoglobin count, number of visceral metastases, ECOG performance status, primary diagnosis, and number of bone metastases. Nevertheless, survival estimate was accurate in predicting actual survival in only 33 (18%) of 181 patients. CONCLUSION: A better means of prognostication is needed. In this article, we present a sliding scale for this purpose.
PURPOSE: To determine if osteosarcoma cells express chemokine receptors and if their presence or absence relates to clinical features. EXPERIMENTAL DESIGN: Using fluorescent quantitative real-time PCR, the pattern of 17 chemokine receptors in 3 osteosarcoma cell lines and 68 osteosarcoma patient samples was analyzed. RESULTS: The expression of the chemokine receptors was generally low among the cell lines. In the high-grade osteosarcoma patient samples (n = 47), CXCR4 was the most commonly expressed (63%) and its expression level was inversely correlated to overall survival (P < 0.0001), event-free survival (P < 0.001), and metastasis-free survival (MFS; P = 0.002). There was also a correlation between the expression level of CXCR4 and the presence of metastasis at diagnosis (P = 0.002). CCR7 was expressed in 43% of the samples and its expression level was inversely correlated with overall survival (P = 0.03) and MFS (P = 0.007). CCR10 mRNA expression level was inversely correlated with MFS (P = 0.009). There was no association between the expression of CXCR4, CCR7, and CCR10. Of the 26 samples studied for stromal cell-derived factor-1 expression, 77% expressed it, but there was no correlation with the clinical variables or CXCR4 expression. Multivariate analysis revealed that mRNA expression level of CXCR4 was the only significant variable for overall survival (P = 0.0006), event-free survival (P = 0.004), and MFS (P = 0.025). CONCLUSIONS: These data suggest that CXCR4 could be useful as a prognostic factor and as a predictor of potential metastatic development in osteosarcoma. If further studies confirm that it is relevant to metastases in this disease, it could represent a new therapeutic target.
PURPOSE: This study investigates the effect of constitutively raised interstitial fluid pressure on osteosarcoma physiology and chemosensitivity. EXPERIMENTAL DESIGN: We did pressure and blood flow assessments at the time of open biopsy in patients with the diagnosis of high-grade osteosarcoma and correlated this to survival and chemotherapy-associated tumor necrosis. Osteosarcoma cell lines were then evaluated for proliferative and therapeutic indices in a replicated high-pressure environment. RESULTS: Sixteen osteosarcomas in vivo were assessed and exhibited elevated interstitial fluid pressures (mean 35.2 +/- SD, 18.6 mmHg). This was not associated with significantly impeded blood flow as measured by a Doppler probe at a single site (P < 0.12). Nonetheless, greater chemotherapy-associated necrosis and associated longer survival were seen in tumors with higher interstitial fluid pressures (P < 0.05). In vitro, cells undergo significant physiologic changes under pressure. Osteosarcoma cell lines grown in a novel hydrostatically pressurized system had variable cell line-specific growth proportional to the level of pressure. They were more proliferative as indicated by cell cycle analysis with more cells in S phase after 48 hours of pressurization (P < 0.01). There was a significant elevation in the cell cycle-related transcription factors E2F-1 (P < 0.03) and E2F-4 (P < 0.002). These changes were associated with increased chemosensitivity. Cells tested under pressure showed an increased sensitivity to cisplatin (P < 0.00006) and doxorubicin (P < 0.03) reminiscent of the increased chemotherapy-associated necrosis seen in tumors with higher interstitial fluid pressure in the clinical study. CONCLUSIONS: The results of this study suggest that cells in the in vivo pressurized environment are at a higher state of regenerative activity than is demonstrable in conventional cell culture systems. Variations in tumor interstitial fluid pressure have the potential to alter chemotherapeutic effects.
Osteosarcoma is the most common malignant bone tumor in children. Osteosarcoma patients who respond poorly to chemotherapy are at a higher risk of relapse and adverse outcome. Therefore, it was the aim of this study to identify prognostic factors at the time of diagnosis to characterize the genes predictive of poor survival outcome and to identify potential novel therapeutic targets. Expression profiling of 30 osteosarcoma diagnostic biopsy samples, 15 with inferior necrosis following induction chemotherapy (Huvos I/II) and 15 with superior necrosis following induction chemotherapy (Huvos III/IV), was conducted using Affymetrix U95Av2 oligonucleotide microarrays. One hundred and four genes were found to be statistically significant and highly differentially expressed between Huvos I/II and III/IV patients. Statistically significant genes were validated on a small independent cohort comprised of osteosarcoma xenograft tumor samples. Markers of Huvos I/II response predominantly were gene products involved in extracellular matrix (ECM) microenvironment remodeling and osteoclast differentiation. A striking finding was the significant decrease in osteoprotegerin, an osteoclastogenesis inhibitory factor. Additional genes involved in osteoclastogenesis and bone resorption, which were statistically different, include annexin 2, SMAD, PLA2G2A, and TGFbeta1. ECM remodeling genes include desmoplakin, SPARCL1, biglycan, and PECAM. Gene expression of select genes involved in tumor progression, ECM remodeling, and osteoclastogenesis were validated via quantitative reverse transcription-PCR in an independent cohort. We propose that osteosarcoma tumor-driven changes in the bone microenvironment contribute to the chemotherapy-resistant phenotype and offer testable hypotheses to potentially enhance therapeutic response.
PURPOSE: Mutations of the TP53 gene have been associated with resistance to chemotherapy as well as poor prognosis in many different malignancies. This is the first prospective study of the prognostic value of somatic TP53 mutations in patients with newly diagnosed extremity osteosarcoma. PATIENTS AND METHODS: One hundred ninety-six patients with high-grade, nonmetastatic osteosarcoma of the extremities were enrolled from seven tertiary care institutions and observed prospectively for tumor recurrence (median follow-up duration, 44 months). All patients received neoadjuvant or adjuvant chemotherapy and surgery. Tumors were analyzed for the presence of TP53 mutations by polymerase chain reaction single-strand conformation polymorphism analysis and direct DNA sequencing. The association of the status of the TP53 gene with the risk of systemic recurrence was examined using survival analyses with traditional and histologic markers as prognostic factors. RESULTS: Patient age was the only factor that varied with TP53 gene status (P = .05). No relationship was identified between TP53 status and systemic relapse (relative risk, 1.24; P = .41). Analyses based on missense or nonsense mutations gave similar results (P > .10). In multivariate analysis, large (> 9 cm) tumor size (relative risk, 1.9; P = .006) and poor histologic response (< or = 90% necrosis) to chemotherapy (relative risk, 2.14; P = .02) were the only significant independent predictors of systemic outcome. CONCLUSION: We found no evidence that TP53 mutations predict for development of metastases in patients with high-grade osteosarcoma. Identification of other genes that influence chemotherapy response and clinical outcome in osteosarcoma is needed to facilitate further improvements in patient outcomes.