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Osteosarcoma is the most common primary malignant osseous neoplasm, constituting approximately 35% of skeletal malignancies. The different subtypes of osteosarcoma are differentiated based on clinical, histologic, and radiographic data, as well as the variable amount of osteoid produced by malignant cells. The epithelioid osteosarcoma subtype accounts for only 5.7% of all osteosarcomas and portends an extremely poor prognosis. The 5-year survival rate for patients with epithelioid osteosarcoma treated with surgery (with or without chemotherapy) is 13.5%. This is in direct contrast to the >70% ten-year survival rate of conventional osteosarcoma treated with surgery and chemotherapy. This article presents a fatal case of epithelioid osteosarcoma in an 11-year-old girl with right knee pain of 6 months' duration. Biopsy demonstrated morphologic findings consistent with high-grade osteosarcoma with epithelioid features. The epithelioid component was positive for vimentin and CD99; however, fluorescent in situ hybridization for the (11;22) translocation was negative. In this case, the epithelioid cells failed to respond to conventional or subsequent experimental chemotherapy for osteosarcoma and eventual metastasized to the lymph nodes and lungs despite multiple ablative surgeries. This case report supports the concept of carcinosarcoma with malignant cells lines arising from 2 different cellular lineages or a common cellular precursor. The epithelial component was more aggressive than the cells of mesenchymal origin, highlighting the need for continued research and a more favorable outcome for this rare subset of osteosarcoma. [ABSTRACT FROM AUTHOR]

Purpose: Bone tumors are common in the distal femur and often treated with intralesional curettage. The optimal method of stabilization of large distal femoral defects after curettage remains unclear. The goal of this study is to compare stabilization techniques for large distal femoral defects., Methods: Large defects (60 cm 3 ) were milled in the distal lateral metaphysis of 45 adult composite sawbone femurs. The defect was either (1) left untreated or reconstructed with (2) locked plate fixation, (3) calcium phosphate cement packing, or (4) locked plate fixation with calcium phosphate cement packing, or (5) polymethylmethacrylate packing. Each specimen then underwent axial and torsional stiffness testing followed by torsional loading to failure. The data were analyzed using ANOVA with Tukey-Kramer post-hoc analysis., Results: The calcium phosphate cement filled defect with a locked plate was the stiffest construct in axial and torsional loading as well as the strongest in torque to failure. However, this difference only reached significance with respect to all other groups in torque to failure testing. The calcium phosphate cement filled defect with a locked plate was significantly stiffer than three of the four other groups in both axial and torsional stiffness testing., Conclusions: These results indicate that calcium phosphate cement, with or without the addition of locked plate fixation, may provide improved construct stability under time zero testing conditions. This result warrants further testing under cyclic loading condition and consideration for fixation of large femoral metaphyseal defects in future clincal trails., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Despite effective local therapy with surgery and radiotherapy (RT), ~50 % of patients with high-grade soft tissue sarcoma (STS) will relapse and die of disease. Since experimental data suggest a significant synergistic effect when antiangiogenic targeted therapies such as sorafenib are combined with RT, we chose to evaluate preoperative combined modality sorafenib and conformal RT in a phase I/II trial among patients with extremity STS amenable to treatment with curative intent., Methods: For the phase I trial, eight patients with intermediate- or high-grade STS >5 cm in maximal dimension or low-grade STS >8 cm in maximal dimension received concomitant sorafenib (dose escalation cohort 1:200 twice daily, cohort 2:200/400 daily) and preoperative RT (50 Gy in 25 fractions). Sorafenib was continued during the entire period of RT as tolerated. Surgical resection was completed 4-6 weeks following completion of neoadjuvant sorafenib/RT. Three sorafenib dose levels were planned. Primary endpoints of the phase I trial were maximal tolerated dose and dose-limiting toxicity (DLT)., Results: Eight patients were enrolled in the phase I (five females, median age 44 years, two high-grade pleomorphic, two myxoid/round cell liposarcoma, four other). Median tumor size was 16 cm (range 8-29), and all tumors were located in the lower extremity. Two of five patients treated at dose level 2 developed DLT consisting of grade 3 rash not tolerating drug reintroduction. Other grade 3 side effects included anemia, perirectal abscess, and supraventricular tachycardia. Radiation toxicity (grade 1 or 2 dermatitis; N = 8) and post-surgical complications (three grade 3 wound complications) were comparable to historical controls and other series of preoperative RT monotherapy. Complete pathologic reponse (≥95 % tumor necrosis) was observed in three patients (38 %)., Conclusion: Neoadjuvant sorafenib in combination with RT is tolerable and appears to demonstrate activity in locally advanced extremity STS. Further study to determine efficacy at dose level 1 is warranted. (ClinicalTrials.gov identifier NCT00805727).

The optimal management of pathologic long bone lesions remains a challenge in orthopedic surgery. The goal of the current study was to investigate the effect of defect depth on the torsional properties of the distal femur. A laterally placed distal metaphyseal cylindrical defect was milled in the cortex of the distal femur in 20 composite models. The proximal extent of the defects was constant. By decreasing the radius of the cylinder that intersected this predefined cord, 4 different radii defining 4 different depths of resection of the distal femur were created for testing: 17%, 33%, 50%, and 67% cortical defects, when normalized to the width of the femur at the level of resection. Each femur was mounted into a hydraulic axial/torsion materials testing machine and each specimen underwent torsional stiffness testing and torsional failure in external rotation. The specimens with less than a 33% cortical loss consistently demonstrated a superiorly oriented spiral fracture pattern, while the specimens with greater than a 50% cortical loss consistently demonstrated an inferiorly oriented transverse fracture pattern. The cortical defects were all statistically (P<.05) less stiff in torsion as the defect grew larger. There was a strong linear correlation between the mean torsional stiffness and cortical defect size (r(2)=0.977). This observation is supported by finite element analysis. The amount of femur remaining is crucial to stability. This biomechanical analysis predicts a critical loss of torsional integrity when a cortical defect approaches 50% of the width of the femur., (Copyright 2014, SLACK Incorporated.)

EDUCATIONAL OBJECTIVES As a result of reading this article, physicians should be able to: 1. Identify at-risk populations for giant cell tumor of bone. 2. Recognize the biology that drives giant cell tumor of bone. 3. Describe modern surgical and adjuvant techniques to effectively treat giant cell tumor of bone. 4. Recognize the complications associated with radiation therapy, poor resection, and adjuvant treatments. Giant cell tumor of bone (GCT) is a benign, locally aggressive bone tumor. Giant cell tumor of bone primarily affects the young adult patient population. The natural history of GCT is progressive bone destruction leading to joint deformity and disability. Surgery is the primary mode of treatment, but GCT has a tendency to recur locally despite a range of adjuvant surgical options. Pulmonary metastasis has been described. However, systemic spread of GCT rarely becomes progressive, leading to death. This review presents the clinicopathologic features of GCT and a historical perspective that highlights the current rationale and controversies regarding the treatment of GCT., (Copyright 2014, SLACK Incorporated.)

Importance: Although prospective randomized data are available to guide the multidisciplinary management of soft tissue sarcoma (STS) of the extremities, controversy exists regarding adjuvant chemotherapy and radiation therapy., Objective: To determine if clinical specialty introduces bias in recommendations for multimodality treatment of STS., Design: Electronic survey., Setting: Database of active members of the American Society of Clinical Oncology, the Society of Surgical Oncology, and the Connective Tissue Oncology Society., Participants: Members of specialty oncology societies with an active interest in STS., Exposure: Physician specialty., Main Outcomes and Measures: Survey responses regarding the multidisciplinary management of STS were scored on a 5-point Likert scale and analyzed using analysis of variance., Results: The questionnaire was completed by 320 of 490 potential respondents (65%), including medical (18%), radiation (8%), orthopedic (22%), and surgical oncologists (45%). Respondents concurred on the use of radiation therapy for margins positive for tumor, for high-grade tumors, for improvement in local control, for tumors larger than 10 cm, and for tumors in close proximity to a neurovascular bundle. Respondents diverged on the use of radiation therapy for tumors 5 to 10 cm in size, for low-grade tumors, for radiation-associated STS, and for survival benefit. Only radiation oncologists felt that radiation therapy was underutilized as a treatment modality (mean [SEM] Likert scale score, 2.44 [0.12]; P < .001). There was agreement on the use of chemotherapy for synovial sarcoma, for high-grade tumors, for tumors larger than 10 cm, for patients younger than 50 years of age, and for survival benefit. Medical oncologists were more likely to recommend chemotherapy for margins positive for tumor (mean [SEM] score, 3.12 [0.12]; P = .03) and for improvement in local control (mean [SEM] score, 2.91 [0.12] P = .08). Surgical oncologists placed the least emphasis on chemotherapy in the overall treatment plan (mean [SEM] score, 2.60 [0.07]; P = .001)., Conclusions and Relevance: Specialty bias exists in adjuvant treatment recommendations for STS. This highlights the importance of multidisciplinary STS tumor boards and interdisciplinary care to facilitate consensus decision making for individual patients.

Although pathologic response to neoadjuvant chemotherapy is highly correlated with survival among patients with osteosarcoma, there are currently no established molecular markers to predict response to chemotherapy. The objective of this study was to investigate the relationship of P16 expression in pretreatment osteosarcoma tumors to pathologic necrotic response after neoadjuvant chemotherapy. A tissue microarray was created from paraffin-embedded pretreatment biopsy specimens of 40 patients with osteosarcoma. Immunohistochemistry was performed with commercially available P16 monoclonal mouse antibody. Expression of P16 was defined as nuclear staining in 30% or greater of cells. Percent tumor necrosis was measured in postchemotherapy resection specimens per established protocols, and 90% or greater tumor necrosis was considered "good." Data were abstracted on age, sex, tumor site, and histologic subtype. Univariate and multivariate analyses were performed. The median age was 15 years, 52% were female, and 35% of tumors were located in the femur. P16 expression was present in 62%. Median posttreatment tumor necrosis was 90%, and 55% of patients experienced "good" chemotherapy response (≥90% necrosis). On univariate analysis, P16 expression correlated positively with median percent necrosis and "good" chemotherapy response (P=.004 and .003, respectively). On logistic regression analysis, P16 expression was independently associated with chemotherapy response after controlling for age, subtype, sex, and location (odds ratio, 43.5; 95% confidence interval, 2.64-708.9; P=.008). In summary, immunohistochemical expression of P16 significantly correlates with chemotherapy response in osteosarcoma. P16 expression may be a useful biomarker to guide treatment selection., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Unlabelled: We sought to determine if complete pathological necrosis (pathCR) predicts favorable oncological outcome in soft tissue sarcoma (STS) patients receiving pre-operative radiation monotherapy (RT)., Patients and Methods: We evaluated 30 patients with primary STS treated with neoadjuvant RT followed by definitive resection, from 2000 to 2010 at our institution. We defined ≥ 95% tumor necrosis as pathCR., Results: There were 22 STS of the extremities (73%), 7 of the retroperitoneum (23%), and 1 (4%) of the trunk. The median pathological percentage of tumor necrosis was 35% (range 5-100%) with three tumors (10%) demonstrating pathCR. With a median follow-up of 40 months, the 5-year local recurrence-free survival (LRFS), distant recurrence-free survival (DRFS), and overall survival (OS) for the entire cohort were 100%, 61% ± 11%, and 69% ± 11%, respectively. Among patients with pathCR, 3-year DRFS was 100% compared to 63±11% in patients without pathCR (p=0.28)., Conclusion: Following neoadjuvant RT for STS, pathCR is associated with a clinically but not statistically significant 37% improvement in 3-year DRFS.

Background: Although well-differentiated liposarcoma (WD Lipo) is a low grade neoplasm with a negligible risk of metastatic disease, it can be locally aggressive. We hypothesized that survival for WD Lipo varies significantly based on tumor location., Methods: We identified 1266 patients with WD Lipo in the Surveillance, Epidemiology, and End Results database from 1988-2004. After excluding patients diagnosed by autopsy only, those lacking histologic confirmation, those lacking data on tumor location, and those with metastatic disease or unknown staging information, we arrived at a final study cohort of 1130 patients. Clinical, pathologic, and treatment variables were analyzed for their association with overall survival (OS) and disease-specific survival (DSS) using Kaplan-Meier analysis and Cox proportional hazards multivariate models., Results: Mean age was 61 y (± 14.6), 72.2% were white, and 60.4% were male. Eighty-one percent of patients were treated with surgical therapy alone, 4.6% were treated with radiotherapy (RT) alone, and 12.9% were treated with both surgery and RT. Extremity location was most common (41.6%), followed by trunk (29%), retroperitoneal/intra-abdominal (RIA, 21.6%), thorax (4.2%), and head/neck (3.6%). With a median follow-up of 45 mo, median OS was 115 mo (95% confidence interval [CI] 92-138 mo) for RIA tumors compared to not reached for other tumor locations (P = 0.002). On multivariate analysis, increasing age and RIA location both predicted worse OS and DSS while tumor size, race, sex, receipt of RT, and Surveillance, Epidemiology, and End Results (SEER) stage did not. Tumor size became a significant predictor of worse DSS, but not OS, only when site, SEER stage, and extent of resection were removed from the multivariate model. Non-RIA locations, including extremity, experienced statistically similar OS, but 5-y DSS for trunk location was intermediate [92.3%, (95% CI 88.5%-96.1%) compared with 98.0% (95% CI, 96.2%-99.8%) for extremity and 86.6 (95% CI 81.1%-92.1%) for RIA, P < 0.001]., Conclusions: Among patients with WD Lipo, RIA location is associated with significantly worse outcomes independent of tumor size. Future studies should focus on the anatomic and biologic reasons for these differences., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: Although multimodal management of extremity soft tissue sarcoma (STS) is the standard of care, considerable variation exists in the sequencing of radiotherapy (RT) or chemotherapy (CT). Our goal was to identify factors responsible for this variation., Methods: Members of specialty societies with an interest in STS were emailed a questionnaire about multimodal treatment of STS. Survey responses were scored on a 5-point Likert scale (1 = always preoperative and 5 = always postoperative) and analyzed by specialty, years in practice, and percentage of practice consisting of STS., Results: The questionnaire was completed by 320 (65%) of 490 physicians, including medical oncologists (18%), radiation oncologists (8%), orthopedic oncologists (22%), surgical oncologists (45%), and others (7%). Respondents were evenly split on the use of neoadjuvant RT (mean 3.03 ± 0.06) and showed a slight preference for neoadjuvant CT (2.89 ± 0.06). Radiation oncologists (2.52 ± 0.18), physicians with a >75% STS practice (2.58 ± 0.17), and those in practice <5 years (2.79 ± 0.12) preferred neoadjuvant RT. Neoadjuvant CT was preferred by orthopedic oncologists (2.62 ± 0.12) and physicians with >75% STS practice (2.51 ± 0.16). Factors influencing the choice for neoadjuvant RT were well-defined treatment volume, increased acute morbidity, and decreased late morbidity, while for CT, they were in-situ disease monitoring and early treatment of micrometastases., Conclusions: Treatment sequencing in STS is influenced by specialty and clinical experience, with no clear consensus. These patterns may reflect the recent trend toward regionalization of STS care.

Background: Histologic grade, completeness of resection, and presence of metastases are traditionally regarded as the primary factors in predicting survival for retroperitoneal soft tissue sarcoma (RPSTS). We sought to examine the importance of histologic type as a prognostic factor among patients with RPSTS., Methods: We identified 2337 cases of RPSTS in the Surveillance, Epidemiology, and End Results (SEER) database from 1988 to 2004. After excluding 273 cases of age <18, identification by autopsy only, or absence of histologic confirmation, we arrived at a final study cohort of 2064 patients. Overall survival (OS) and disease-specific survival (DSS) were estimated using the Kaplan-Meier method. Multivariate analysis was performed using a Cox proportional hazards model, adjusting for age, gender, race, histologic type, histologic grade, tumor size, extent of resection, and SEER summary stage., Results: Among 33 histologic types, leiomyosarcoma (28.7%), well-differentiated/dedifferentiated liposarcoma (20.3%), liposarcoma not otherwise specified (NOS) (11.9%), malignant fibrous histiocytoma (MFH-11.0%), and sarcoma NOS (10.7%) were the most prevalent. Grade distribution was low, 24.2%; intermediate, 16%; high 34.3%, and unknown, 25.5%. Surgery was performed in 85.8%, and radiotherapy was administered to 22.8%. With a median follow-up of 38 mo, median OS was 78, 35, 25, 18, and 10 mo for liposarcoma, leiomyosarcoma, other histologies, MFH, and sarcoma NOS, respectively (P < 0.0001). Median DSS was 120, 53, not reached, 30, and 13 mo for liposarcoma, leiomyosarcoma, other histologies, MFH, and sarcoma NOS, respectively (P < 0.0001). On multivariate analysis, histologic type was associated with statistically significant differences in both OS and DSS., Conclusions: Histologic type is an important predictor of survival in RPSTS., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Osteoid osteoma is the most common bone-producing tumor that typically presents with "throbbing night pain" and that improves dramatically with use of low-dose salicylates. Few cases of pelvic osteoid osteoma have been reported, and most have involved patients younger than age 30. Surgical excision classically has been the treatment of choice, but, recently, less invasive modalities, including radiofrequency ablation, have begun to supplant surgical management of osteoid osteoma, resulting in a decrease in the need for definitive surgical diagnosis and treatment. We present a rare case of osteoid osteoma in the pelvis of a woman older than age 30.

Background: The benefit of radiation therapy (RT) among patients with retroperitoneal sarcoma (RPS) is controversial. We performed a retrospective analysis of the effect of RT on survival among RPS patients using a nationwide cancer registry., Methods: Utilizing data from the Surveillance, Epidemiology, and End Results (SEER) database, we identified 2308 cases of RPS from 1988 to 2004. We excluded 773 cases for age < 18, identification by autopsy only, absence of histologic confirmation, presence of metastatic disease, or lack of surgical intervention. Overall survival (OS) and disease-specific survival (DSS) were estimated using the Kaplan-Meier method. Multivariate analysis was performed using a Cox proportional hazards model, adjusting for significant covariables., Results: Among 1535 patients who met entry criteria, RT was administered to 373 patients (24.3%). The majority of RT (n = 300, 80.4%) was administered postoperatively. Median OS was 60 and 60 mo, respectively, for patients receiving and not receiving RT (P = 0.59). Median DSS was 86 and 117 mo, respectively, for patients receiving and not receiving RT (P = 0.84). On multivariate analysis, younger age, female gender, low and intermediate histologic grade, liposarcoma histology, tumor size 5-10 cm, and completeness of resection all independently predicted better OS and DSS, while RT did not (HR for OS with RT 0.92, 95% CI 0.78-1.09 and HR for DSS with RT 0.96, 95% CI 0.78-1.17). On subgroup analysis by histology, patients with malignant fibrous histiocytoma (MFH) receiving RT demonstrated statistically improved OS (P = 0.002) and DSS (P = 0.01), respectively., Conclusions: With the possible exception of MFH, postoperative RT offers no survival benefit in RPS. Further studies are necessary to determine if the selective application of RT is indicated., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background and Objectives: The practice of aggressive contiguous organ resection (COR) of retroperitoneal sarcoma (RPS) is controversial. We examined rates of 30-day morbidity and mortality following resection of RPS utilizing data from the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database., Methods: From 2005 to 2007, we identified 156 cases of primary malignant neoplasm of the retroperitoneum. Univariate and multivariate analyses were performed using all pre-operative ACS-NSQIP variables for likelihood of post-operative overall morbidity or severe morbidity (composite endpoint including organ space infection, septic shock, acute renal failure requiring dialysis, reoperation, and death). Insufficient events precluded multivariate analysis of mortality as an independent outcome., Results: Overall 30-day morbidity, severe morbidity, and mortality were 26% (N = 40), 11.5% (N = 18), and 1.3% (N = 2), respectively. Fifty-eight patients (37%) underwent COR, most commonly kidney. American Society for Anesthesiologists classification predicted overall morbidity (OR 3.23, 95% CI 1.33-7.84), while increasing operative time predicted severe morbidity (OR 1.38 per hour, 95% CI 1.05-1.81). COR was not associated with increased 30-day overall morbidity (OR 1.38, 95% CI 0.49-3.89) or severe morbidity (OR 0.78, 95% CI 0.05-13.18)., Conclusions: Rates of post-operative morbidity and mortality are acceptable following RPS resection, even in the setting of multi-visceral resection. COR should not be viewed as a contraindication to complete RPS resection., (Copyright © 2010 Wiley-Liss, Inc.)

Background: Limited data exist regarding the radiographic and histologic response of soft tissue sarcoma (STS) to neoadjuvant radiotherapy (RT)., Methods: Between February 2000 and January 2009, a total of 25 patients aged >16 years with intermediate- or high-grade primary STS of all sites were treated with neoadjuvant RT followed by definitive resection. Patients receiving chemoradiotherapy were excluded. Cross-sectional images obtained before and after RT as well as pathologic specimens were reviewed for maximal change in tumor diameter and percentage tumor necrosis, respectively. Clinicopathologic variables were analyzed for their association with pathologic and radiographic response., Results: There were 18 extremity (72%) and 7 retroperitoneal (28%) tumors. Median maximal tumor size was 9 cm (range, 3.3-35 cm), and 88% were of high grade. There were 21 R0 resections (84%) and 4 R1 resections (16%). Radiographically, the median percentage change in tumor diameter was 0% (range, -25 to +86%). By Response Evaluation Criteria in Solid Tumors (RECIST), 5 patients demonstrated progressive disease, 20 demonstrated stable disease, and 0 demonstrated partial/complete response. The median pathologic percentage tumor necrosis was 30% (range, 5-100%). Two tumors (8%) demonstrated near-complete pathologic response (≥95% necrosis). Near-complete pathologic response was associated with favorable oncologic outcomes, although these associations were not statistically significant., Conclusions: Radiologic and near-complete pathologic responses are rare events after preoperative RT for STS. Near-complete pathologic response may be a potentially meaningful surrogate marker for disease outcome and is not predicted by RECIST response. Knowledge of these historical response rates is important for the evaluation of novel neoadjuvant therapies for patients with STS.

The primary goal of treatment for malignant bone and soft tissue tumors of the hand and upper extremity is an oncologic cure. The secondary goal is maintenance of function. Despite recent advances in chemotherapy and radiation techniques, amputation still provides a means for achieving surgical cure for some bone and soft tissue sarcomas. A well planned amputation with attention to level, soft tissue closure, muscle transfer as needed, and nerve handling combined with early fitting of modern prosthetic devices provides patients with a rapid return to normal activity. This article reviews the general principles and specific techniques of amputation in the patient with an upper extremity malignancy.

Purpose: The purpose of this study was to determine the financial efficacy of arthroscopic synovectomy in hemophilia patients with recurrent hemarthroses., Type of Study: Cost-benefit analysis., Methods: A retrospective chart review from 1993 through 1999 yielded 11 cases of arthroscopic synovectomies performed for recurrent hemarthroses at the University of Michigan. There were 7 ankle arthroscopies, 3 elbow arthroscopies, and 1 knee arthroscopy. The average age of the patients was 8 years (range, 4-13 years). All had the severe form of hemophilia A. The average follow-up was 41 months (range, 9-75 months). The preoperative costs were determined by multiplying the number of preoperative bleeds by the dollar amount of the replacement therapy used to treat the hemarthroses. The surgical costs included the surgery itself as well as the hospital stay and the dollar amount of the replacement therapy used in the perioperative period. The total postoperative costs included the surgical costs and the dollar amount of any replacement therapy used to treat any postoperative hemarthroses., Results: The financial benefit of arthroscopic synovectomy was found to be statistically significant when average preoperative cost per month ($7,500) was compared with the average postoperative cost per month ($900), P =.028. Arthroscopic synovectomy was again found to be financially beneficial when the average total preoperative cost ($88,000) was compared with the average total postoperative cost ($24,000), P =.028. The average number of hemarthroses preoperatively was 71 and the average postoperatively was 7, which was statistically significant (P =.028)., Conclusions: In this small series of patients with intermediate follow-up, arthroscopic synovectomy was found to be cost effective in the treatment of patients with recurrent hemarthroses.

Purpose: The purpose of this study was to determine the relative benefits of sparing longitudinal bone growth by fractionation alone compared to pretreatment with amifostine, a chemical that provides differential radioprotection of normal tissues., Methods and Materials: Twenty-four weanling 4-week-old male Sprague-Dawley rats were randomized into 2 overall treatment groups: fractionation alone (n = 12) and amifostine pretreatment (n = 12). The distal femur and proximal tibia in the right leg of each animal were exposed to a therapeutic X-irradiation dose (17.5 Gy total in 3 or 5 fractions) with the contralateral left leg as control. In 12 of the animals, amifostine (100 mg/kg) was administered intraperitoneally 20 min before radiation exposure. Six weeks later, growth was calculated based upon measurement of the bone lengths., Results: Fractionated radiation resulted in a mean percent overall limb growth loss of 21. 1 +/- 7.0%. The addition of amifostine brought the mean percent overall limb growth loss to 16.3% +/- 4.6%, which showed a strong trend toward significance compared to fractionation alone (p = 0. 061). The addition of radioprotection with amifostine to 5 fractions irradiation significantly reduced the femoral and overall percentage growth arrest and limb length discrepancy compared to 5 fractions alone., Conclusions: These results support further investigation of amifostine and other radioprotectants in combination with fractionation for use in growing children requiring radiotherapy to the extremity for malignant tumors.

The radioprotectant compound amifostine (S-2[3-aminopropylamino]-ethylphosphorothioic acid), administered prior to radiotherapy, has been demonstrated to provide differential protection of normal cells from the damaging effects of ionizing radiation. The aim of this pilot was to determine if amifostine could preserve the integrity of, or minimize the damage to, the physis during exposure to radiation in an animal model. Thirty weanling Sprague-Dawley rats were randomized into five groups of six animals each. Groups 1 and 2 received a single exposure to radiation consisting of 12.5 and 17.5 Gy, respectively. Groups 3 and 4 received similar exposures of 12.5 and 17.5 Gy, respectively, but with prior administration of amifostine at 100 mg/kg. Group 5 (control) received neither radiation nor amifostine. At 6 weeks, femoral and tibial lengths were measured in treated and untreated hindlimbs and compared with the baseline lengths to calculate growth. Concordant with previous reports in the literature, the radiation doses of 12.5 and 17.5 Gy reduced net femoral growth in length by a mean of 23% (range = 12-33%, SD = 7.41) and 59% (range = 54-64%, SD = 4.45), respectively, in the irradiated limb. Amifostine reduced anticipated growth loss normally resulting from a single 12.5-Gy radiation dose by 48.9% in the femur, 13.1% in the tibia, and 27.6% overall in the total limb (p < or = 0.05). Similarly, anticipated growth loss from a single 17.5-Gy radiation dose was reduced by 30.8% in the femur, 20.3% in the tibia, and 25.7% overall in the total limb (p < or = 0.05). Amifostine administered prior to clinically relevant radiation exposures significantly reduced the amount of anticipated growth arrest in our animal model.