Survival and failure modes of the Compress® spindle and expandable distal femur endoprosthesis among pediatric patients: A multi-institutional study.

BACKGROUND: Expandable endoprostheses can be used to equalize limb length for pediatric patients requiring reconstruction following large bony oncologic resections. Outcomes of the Compress® Compliant Pre-Stress (CPS) spindle paired with an Orthopedic Salvage System expandable distal femur endoprosthesis have not been reported. METHODS: We conducted a multi-institutional retrospective study of pediatric patients with distal femoral bone sarcomas reconstructed with the above endoprostheses. Statistical analysis utilized Kaplan-Meier survival technique and competing risk analysis. RESULTS: Thirty-six patients were included from five institutions. Spindle survivorship was 86.3% (95% confidence interval [CI], 67.7-93.5) at 10 years. Two patients had a failure of osseointegration (5.7%), both within 12 months. Twenty-two (59%) patients had 70 lengthening procedures, with mean expansions of 3.2 cm (range: 1-9) over 3.4 surgeries. The expandable mechanism failed in eight patients with a cumulative incidence of 16.1% (95% CI, 5.6-31.5) at 5 years. Twenty-nine patients sustained International Society of Limb Salvage failures requiring 63 unplanned surgeries. Periprosthetic joint infection occurred in six patients (16.7%). Limb preservation rate was 91% at 10 years. CONCLUSIONS: There is a high rate of osseointegration of the Compress® spindle among pediatric patients when coupled with an expandable implant. However, there is a high rate of expansion mechanism failure and prosthetic joint infections requiring revision surgery. LEVEL OF EVIDENCE: Level IV, therapeutic study.

What Are Risk Factors for and Outcomes of Late Amputation After Treatment for Lower Extremity Sarcoma: A Childhood Cancer Survivor Study Report.

BACKGROUND: Although pediatric lower extremity sarcoma once was routinely treated with amputation, multiagent chemotherapy as well as the evolution of tumor resection and reconstruction techniques have enabled the wide adoption of limb salvage surgery (LSS). Even though infection and tumor recurrence are established risk factors for early amputation (< 5 years) after LSS, the frequency of and factors associated with late amputation (≥ 5 years from diagnosis) in children with sarcomas are not known. Additionally, the resulting psychosocial and physical outcomes of these patients compared with those treated with primary amputation or LSS that was not complicated by subsequent amputation are not well studied. Studying these outcomes is critical to enhancing the quality of life of patients with sarcomas. QUESTIONS/PURPOSES: (1) How have treatments changed over time in patients with lower extremity sarcoma who are included in the Childhood Cancer Survivor Study (CCSS), and did primary treatment with amputation or LSS affect overall survival at 25 years among patients who had survived at least 5 years from diagnosis? (2) What is the cumulative incidence of amputation after LSS for patients diagnosed with pediatric lower extremity sarcomas 25 years after diagnosis? (3) What are the factors associated with time to late amputation (≥ 5 years after diagnosis) in patients initially treated with LSS for lower extremity sarcomas in the CCSS? (4) What are the comparative social, physical, and emotional health-related quality of life (HRQOL) outcomes among patients with sarcoma treated with primary amputation, LSS without amputation, or LSS complicated by late amputation, as assessed by CCSS follow-up questionnaires, the SF-36, and the Brief Symptom Inventory-18 at 20 years after cancer diagnosis? METHODS: The CCSS is a long-term follow-up study that began in 1994 and is coordinated through St. Jude Children's Research Hospital. It is a retrospective study with longitudinal follow-up of more than 38,000 participants treated for childhood cancer when younger than 21 years at one of 31 collaborating institutions between 1970 and 1999 in the United States and Canada. Participants were eligible for enrollment in the CCSS after they had survived 5 years from diagnosis. Within the CCSS cohort, we included participants who had a diagnosis of lower extremity sarcoma treated with primary amputation (547 patients with a mean age at diagnosis of 13 ± 4 years) or primary LSS (510 patients with a mean age 14 ± 4 years). The LSS cohort was subdivided into LSS without amputation, defined as primary LSS without amputation at the time of latest follow-up; LSS with early amputation, defined as LSS complicated by amputation occurring less than 5 years from diagnosis; or LSS with late amputation, defined as primary LSS in study patients who subsequently underwent amputation 5 years or more from cancer diagnosis. The cumulative incidence of late amputation after primary LSS was estimated. Cox proportional hazards regression with time-varying covariates identified factors associated with late amputation. Modified Poisson regression models were used to compare psychosocial, physical, and HRQOL outcomes among patients treated with primary amputation, LSS without amputation, or LSS complicated by late amputation using validated surveys. RESULTS: More study participants were treated with LSS than with primary amputation in more recent decades. The overall survival at 25 years in this population who survived 5 years from diagnosis was not different between those treated with primary amputation (87% [95% confidence interval [CI] 82% to 91%]) compared with LSS (88% [95% CI 85% to 91%]; p = 0.31). The cumulative incidence of amputation at 25 years after cancer diagnosis and primary LSS was 18% (95% CI 14% to 21%). With the numbers available, the cumulative incidence of late amputation was not different among study patients treated in the 1970s (27% [95% CI 15% to 38%]) versus the 1980s and 1990s (19% [95% CI 13% to 25%] and 15% [95% CI 10% to 19%], respectively; p = 0.15). After controlling for gender, medical and surgical treatment variables, cancer recurrence, and chronic health conditions, gender (hazard ratio [HR] 2.02 [95% CI 1.07 to 3.82]; p = 0.03) and history of prosthetic joint reconstruction (HR 2.58 [95% CI 1.37 to 4.84]; p = 0.003) were associated with an increased likelihood of late amputation. Study patients treated with a primary amputation (relative risk [RR] 2.04 [95% CI 1.15 to 3.64]) and LSS complicated by late amputation (relative risk [RR] 3.85 [95% CI 1.66 to 8.92]) were more likely to be unemployed or unable to attend school than patients treated with LSS without amputation to date. The CCSS cohort treated with primary amputation and those with LSS complicated by late amputation reported worse physical health scores than those without amputation to date, although mental and emotional health outcomes did not differ between the groups. CONCLUSION: There is a substantial risk of late amputation after LSS, and both primary and late amputation status are associated with decreased physical HRQOL outcomes. Children treated for sarcoma who survive into adulthood after primary amputation and those who undergo late amputation after LSS may benefit from interventions focused on improving physical function and reaching educational and employment milestones. Efforts to improve the physical function of people who have undergone amputation either through prosthetic design or integration into the residuum should be supported. Understanding factors associated with late amputation in the setting of more modern surgical approaches and implants will help surgeons more effectively manage patient expectations and adjust practice to mitigate these risks over the life of the patient. LEVEL OF EVIDENCE: Level III, therapeutic study.

Tumor morphology and location associate with immune cell composition in pleomorphic sarcoma.

BACKGROUND: Soft-tissue sarcomas (STS) are a rare group of mesenchymal malignancies that account for approximately 1% of adult human cancer. Undifferentiated pleomorphic sarcoma (UPS) is one of the most common subtypes of adult STS. Clinical stratification of UPS patients has not evolved for decades and continues to rely on tumor-centric metrics including tumor size and depth. Our understanding of how the tumor microenvironment correlates to these clinicopathologic parameters remains limited. METHODS: Here, we performed single-cell flow cytometric immune-based profiling of 15 freshly resected UPS tumors and integrated this analysis with clinical, histopathologic, and outcomes data using both a prospective and retrospective cohort of UPS patients. RESULTS: We uncovered a correlation between physiologic and anatomic properties of UPS tumors and the composition of immune cells in the tumor microenvironment. Specifically, we identified an inverse correlation between tumor-infiltrating CD8 + T cells and UPS tumor size; and a positive correlation between tumor-infiltrating CD8 + T cells and overall survival. Moreover, we demonstrate an association between anatomical location (deep or superficial) and frequency of CD4 + PD1hi infiltrating T cells in UPS tumors. CONCLUSIONS: Our study provides an immune-based analysis of the tumor microenvironment in UPS patients and describes the different composition of tumor infiltrating lymphocytes based on size and tumor depth.

How Often Does Spindle Failure Occur in Compressive Osseointegration Endoprostheses for Oncologic Reconstruction?

BACKGROUND: Compressive osseointegration is a promising modality for limb salvage in distal femoral oncologic tumors. However, few studies have explored short-term survival rates in a large patient cohort of distal femur compressive endoprostheses or highlighted the risk factors for spindle failures. QUESTIONS/PURPOSES: We asked: (1) What is the frequency of compressive osseointegration spindle failure in distal femoral reconstructions? (2) What are the characteristics of rotational failure cases with distal femur compressive osseointegration endoprostheses? (3) What are the risk factors for mechanical and rotational failure of distal femur compressive osseointegration implantation? (4) What are other modalities of failure or causes of revision surgery, which affect patients undergoing distal femur compressive osseointegration implantation for oncologic reconstruction? METHODS: Between 1996 and 2013, 127 distal femoral reconstructions with the Compress(®) prosthesis were performed in 121 patients. During that time, 116 Compress(®) prostheses were implanted for aggressive primary tumors of the distal femur and/or failure of previous oncologic reconstruction. This approach represented approximately 91% of the distal femoral reconstructions performed during that time. Of the patients with prostheses implanted, four patients (four of 116, 3%) had died, and 37 (37 of 116, 32%) were lost to followup before 24 months. The median followup was 84 months (range, 24-198 months), and 71 patients (66% of all patients) were seen within the last 3 years. A retrospective chart review was performed to determine failure modality as defined by radiographs, clinical history, and intraoperative findings. Risk factors including age, sex, BMI, resection length, and perioperative chemotherapy were analyzed to determine effect on spindle and rotational failure rates. Survival analysis was determined using the Kaplan-Meier estimator. Differences in survival between groups were analyzed using the log rank test. Risk factors were determined using Cox proportional hazard modeling. RESULTS: Spindle survival at 5 and 10 years was 91% (95% CI, 82%-95%). Survival rates from rotational failure at 5 and 10 years were 92% (95% CI, 83%-96%); the majority of failures occurred within the first 2 years postoperatively and were the result of a twisting mechanism of injury. With the numbers available, none of the potential risk factors examined were associated with mechanical failure. The 5-year and 10-year all-cause revision-free survival rates were 57% (95% CI, 44%-67%) and 50% (95% CI, 36%-61%), respectively. CONCLUSIONS: Distal femur compressive osseointegration is a viable method for endoprosthetic reconstruction. Rotational failure is rare with the majority occurring early. No variables were found to correlate with increased risk of mechanical failure. More research is needed to evaluate methods of preventing mechanical and rotational failures in addition to other common causes of revision such as infection in these massive endoprosthetic reconstructions. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Secondary malignant neoplasms among children, adolescents, and young adults with osteosarcoma.

BACKGROUND: As patients with osteosarcoma become long-term survivors, increasing attention has turned to the burden of late effects. The goal of the current study was to describe the incidence, characteristics, and outcomes of secondary malignant neoplasms (SMNs) in this population. METHODS: Patients aged birth to 40 years at time of primary diagnosis with osteosarcoma and reported to the Surveillance, Epidemiology, and End Results (SEER) program between 1973 and 2010 were eligible for inclusion in the cohort. Competing risks methods were used to estimate the cumulative incidence of SMNs and potential risk factors for developing an SMN. Standardized incidence ratios (SIR) and overall survival after an SMN were estimated. RESULTS: The SEER database included 3379 patients who were diagnosed with osteosarcoma as their first malignancy. Of these, 89 patients were diagnosed with an SMN. The cumulative incidence of any SMN was 2.1% (95% confidence interval [95% CI], 1.6%-2.7%) at 10 years, 4.0% (95% CI, 3.1%-5.1%) at 20 years, and 7.4% (95% CI, 5.6%-9.5%) at 30 years. The median time from the primary diagnosis to an SMN diagnosis was 6.0 years. The SIR for SMNs for survivors of osteosarcoma compared with the general population was 1.6 (95% CI, 1.0-2.5) for patients diagnosed with osteosarcoma from 1973 through 1985 and 4.7 (95% CI, 3.3-6.4) for patients diagnosed with osteosarcoma from 1986 through 2010, with a 34-fold increased risk of leukemia in this most recent era. The overall survival rate at 5 years for patients with SMNs after a diagnosis of osteosarcoma was 44.5%. CONCLUSIONS: Survivors of osteosarcoma are at an increased risk of developing SMNs compared with the baseline population, with an increased risk noted in patients treated in the more recent era.

Surgical Site Infection Is Not Associated with 1-Year Progression-Free Survival After Endoprosthetic Reconstruction for Lower-Extremity Osteosarcoma: A Secondary Analysis of PARITY Study Data.

BACKGROUND: Although there is evidence suggesting that postoperative infection confers a survival benefit in osteosarcoma treated with resection and endoprosthetic reconstruction, there have been no prospective studies to date to support these findings. This secondary analysis of Prophylactic Antibiotic Regimens in Tumor Surgery (PARITY) study data examines the relationship between surgical site infection (SSI) and disease progression within 12 months after limb salvage surgery. METHODS: The PARITY trial was an international, multicenter, prospective randomized controlled trial of 604 patients who underwent resection of a lower-extremity bone tumor and endoprosthetic reconstruction. Our primary outcome was progression-free survival (PFS) at 1 year following surgery among the patients with osteosarcoma. Subgroup analyses by disease stage at presentation and infection severity were also performed. Cox proportional hazard models were employed to examine the association between clinical and tumor characteristics, SSI, and PFS. Kaplan-Meier analysis was used to determine the effect of SSI on PFS. RESULTS: The 274 PARITY patients with osteosarcoma were included in this secondary analysis. Thirty-two (11.7%) of the patients presented with metastasis at baseline; 53 (19.3%) of the patients developed an SSI. There was no difference in 1-year PFS between patients with and without SSI. There was no decreased risk of disease progression at 1 year in patients with localized disease at baseline who developed an SSI (hazard ratio [HR] = 1.21; 95% confidence interval [CI] = 0.64 to 2.28). Infection was associated with increased disease progression at 1 year in patients with baseline metastases (HR = 4.26; 95% CI = 1.11 to 16.3). CONCLUSIONS: No positive association was detected between postoperative infection and PFS at 1 year following surgery in this secondary analysis of prospective data. However, this analysis suggests infection could be a risk factor for early disease progression in patients with baseline metastases, and future investigations may better elucidate the association between disease burden and the host immune response to advance immunotherapeutic strategies for osteosarcoma. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

Aseptic failure: how does the Compress(®) implant compare to cemented stems?

BACKGROUND: Failure of endoprosthetic reconstruction with conventional stems due to aseptic loosening remains a challenge for maintenance of limb integrity and function. The Compress(®) implant (Biomet Inc, Warsaw, IN, USA) attempts to avoid aseptic failure by means of a unique technologic innovation. Though the existing literature suggests survivorship of Compress(®) and stemmed implants is similar in the short term, studies are limited by population size and followup duration. QUESTIONS/PURPOSES: We therefore compared (1) the rate of aseptic failure between Compress(®) and cemented intramedullary stems and (2) evaluated the overall intermediate-term implant survivorship. METHODS: We reviewed 26 patients with Compress(®) implants and 26 matched patients with cemented intramedullary stems. The patients were operated on over a 3-year period. Analysis focused on factors related to implant survival, including age, sex, diagnosis, infection, aseptic loosening, local recurrence, and fracture. Minimum followup was 0.32 years (average, 6.2 years; range, 0.32-9.2 years). RESULTS: Aseptic failure occurred in one (3.8%) patient with a Compress(®) implant and three (11.5%) patients with cemented intramedullary stems. The 5-year implant survival rate was 83.5% in the Compress(®) group and 66.6% in the cemented intramedullary stem group. CONCLUSIONS: The Compress(®) implant continues to be a reliable option for distal femoral limb salvage surgery. Data regarding aseptic failure is encouraging, with equivalent survivorship against cemented endoprosthetic replacement at intermediate-term followup. LEVEL OF EVIDENCE: Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Use of three-dimensional printing and intraoperative navigation in the surgical resection of metastatic acetabular osteosarcoma.

A 21-year-old man underwent a joint-preserving posterior acetabular resection of metastatic osteosarcoma using a three-dimensional (3D) printed model and intraoperative navigation. The combined application of these advanced technologies can allow for surgical planning of osteotomies involving complex anatomy and help guide resections intraoperatively. They can maximise the achievement of negative oncological margins, preservation of native hip stability and critical neurovascular structures, and optimal postoperative function in an effort to resect all clinically evident disease. For this particular patient, with secondary bony metastases, they allowed for a safe and well-tolerated procedure that ultimately afforded him palliative benefit, improved quality of life and, conceivably, prolonged survival in the setting of a devastating prognosis. Although he, sadly, has since passed away, he survived for over 2 years after initial metastasis with preserved hip stability and the ability to graduate college, stay active and maintain a quality of life that addressed his goals of care.

Teriparatide, vitamin D, and calcium healed bilateral subtrochanteric stress fractures in a postmenopausal woman with a 13-year history of continuous alendronate therapy.

BACKGROUND: Oral bisphosphonates comprise the most widely prescribed class of antiosteoporotic drugs. Recent reports, however, propose a link between prolonged bisphosphonate use and atypical, low-energy, subtrochanteric fractures. OBJECTIVES: The aim was to describe the clinical course of a patient treated long-term with alendronate who developed subtrochanteric stress fractures and to propose a hypothesis to explain teriparatide's potential contribution in healing the patient's stress fractures. RESULTS: Magnetic resonance imaging (MRI) showed classical bilateral stress fractures of the mid-femora. Baseline serum 25-hydroxyvitamin D(3) was low; bone-specific alkaline phosphatase was slightly increased; serum carboxyterminal cross-linking telopeptide of bone collagen and urine aminoterminal cross-linking telopeptide of bone collagen were low to normal, as was serum osteocalcin. Dual-energy x-ray absorptiometry showed osteopenic vertebral bone mineral density and osteoporotic hip values. Treatment with large doses of oral vitamin D increased serum 25-hydroxyvitamin D(3) to normal within 2 months, after which it remained in the normal range with maintenance doses. Thigh pain, present as an initial symptom, intensified, and the MRI appearance of the fractures worsened. Teriparatide treatment commenced, and 6 months later, a repeat MRI showed decreased edema at the fracture sites with faint cortical bridging. Thigh pain and lower limb weakness disappeared over the next year, and complete fracture healing was established (MRI). CONCLUSIONS: Based upon the chronology of fracture healing in our patient and published evidence that teriparatide heals stress fractures in a rat model, we think that teriparatide was probably primary in this patient's positive response to therapy, with calcium, vitamin D therapy, and alendronate discontinuation playing secondary roles.