Complete tumor necrosis after neoadjuvant chemotherapy defines good responders in patients with Ewing sarcoma.

BACKGROUND: Survival in patients who have Ewing sarcoma is correlated with postchemotherapy response (tumor necrosis). This treatment response has been categorized as the response rate, similar to what has been used in osteosarcoma. There is controversy regarding whether this is appropriate or whether it should be a dichotomy of complete versus incomplete response, given how important a complete response is for in overall survival of patients with Ewing sarcoma. The purpose of this study was to evaluate the impact that the amount of chemotherapy-induced necrosis has on (1) overall survival, (2) local recurrence-free survival, (3) metastasis-free survival, and (4) event-free survival in patients with Ewing sarcoma. METHODS: In total, 427 patients who had Ewing sarcoma or tumors in the Ewing sarcoma family and received treatment with preoperative chemotherapy and surgery at 10 international institutions were included. Multivariate Cox proportional-hazards analyses were used to assess the associations between tumor necrosis and all four outcomes while controlling for clinical factors identified in bivariate analysis, including age, tumor volume, location, surgical margins, metastatic disease at presentation, and preoperative radiotherapy. RESULTS: Patients who had a complete (100%) tumor response to chemotherapy had increased overall survival (hazard ratio [HR], 0.26; 95% CI, 0.14-0.48; p < .01), recurrence-free survival (HR, 0.40; 95% CI, 0.20-0.82; p = .01), metastasis-free survival (HR, 0.27; 95% CI, 0.15-0.46; p ≤ .01), and event-free survival (HR, 0.26; 95% CI, 0.16-0.41; p ≤ .01) compared with patients who had a partial (0%-99%) response. CONCLUSIONS: Complete tumor necrosis should be the index parameter to grade response to treatment as satisfactory in patients with Ewing sarcoma. Any viable tumor in these patients after neoadjuvant treatment should be of oncologic concern. These findings can affect the design of new clinical trials and the risk-stratified application of conventional or novel treatments.

Distribution and Rate of Myxoid Liposarcoma Spine Metastases: Impact on Surveillance Imaging.

BACKGROUND: Myxoid liposarcoma (LPS) has a unique tendency to spread to extrapulmonary sites, including osseous sites such as the spine, and adjacent sites such as the paraspinous tissue. No clear consensus exists to guide the approach to imaging in these patients. OBJECTIVE: The aim of this study was to investigate the rate and distribution of spine metastases in patients with myxoid LPS and detection modality. METHODS: Records of all patients with myxoid LPS evaluated at our sarcoma center were retrospectively reviewed. Disease patterns and imaging modality utilization were analyzed. RESULTS: Between 2000 and 2020, 164 patients with myxoid LPS were identified. The majority (n = 148, 90%) presented with localized disease, with half (n = 82, 50%) of all patients developing metastases or recurrence during their disease course. With a median follow-up of 69.2 months, spine/paraspinous metastases developed in 38 patients (23%), of whom 35 (92%) already had synchronous, non-spine metastases. Spine disease was only visible on magnetic resonance imaging (MRI), as opposed to other imaging modalities, for over one-quarter of patients with spine metastases (n = 10). For patients with metastatic disease, spine metastases were associated with worse median overall survival (2.1 vs. 8.7 years, p < 0.001). CONCLUSION: Spine metastases occurred in nearly one-quarter of patients with myxoid LPS and represented an advanced disease state, as they primarily presented in the setting of synchronous, non-spine metastases, and were associated with worse overall survival. Routine surveillance with spine MRI in patients with localized disease likely provides no benefit but may be considered in those with known metastatic disease.

Albumin and Survival in Extremity Metastatic Bone Disease: An Analysis of Two Independent Datasets.

INTRODUCTION: Numerous prognostication models have been developed to estimate survival in patients with extremity metastatic bone disease, but few include albumin despite albumin's role in malnutrition and inflammation. The purpose of this study was to examine two independent datasets to determine the value for albumin in prognosticating survival in this population. MATERIALS AND METHODS: Extremity metastatic bone disease patients undergoing surgical management were identified from two independent populations. Population 1: Retrospective chart review at two tertiary care centers. Population 2: A large, national, North American multicenter surgical registry with 30-day follow-up. Bivariate and multivariate analyses were used to examine albumin's value for prognostication at 1-, 3-, and 12-month after surgery. RESULTS: In Population 1, 1,090 patients were identified with 1-, 3-, and 12-month mortality rates of 95 (8.8%), 305 (28.9%), and 639 (62.0%), respectively. In Population 2, 1,675 patients were identified with one-month postoperative mortality rates of 148 (8.8%). In both populations, hypoalbuminemia was an independent prognostic factor for mortality at 30 days. In the institutional set, hypoalbuminemia was additionally associated with 3- and 12-month mortality. CONCLUSIONS: Hypoalbuminemia is a marker for mortality in extremity metastatic bone disease. Further consideration of this marker could improve existing prognostication models in this population. LEVEL OF EVIDENCE: III.

Diagnoses, treatment, and oncologic outcomes in patients with calcaneal malignances: Case series, systematic literature review, and pooled cohort analysis.

BACKGROUND AND OBJECTIVES: Malignant tumors of the calcaneus are rare but pose a treatment challenge. AIMS: (1) describe the demographics of calcaneal malignancies in a large cohort; (2) describe survival after amputation versus limb-salvage surgery for high-grade tumors. METHODS: Study group: a "pooled" cohort of patients with primary calcaneal malignancies treated at two cancer centers (1984-2015) and systematic literature review. Kaplan-Meier analyses described survival across treatment and diagnostic groups; proportional hazards modeling assessed mortality after amputation versus limb salvage. RESULTS: A total of 131 patients (11 treated at our centers and 120 patients from 53 published studies) with a median 36-month follow-up were included. Diagnoses included Ewing sarcoma (41%), osteosarcoma (30%), and chondrosarcoma (17%); 5-year survival rates were 43%, 73% (70%, high grade only), and 84% (60%, high grade only), respectively. Treatment involved amputation in 52%, limb salvage in 27%, and no surgery in 21%. There was no difference in mortality following limb salvage surgery (vs. amputation) for high-grade tumors (HR 0.38; 95% CI 0.14-1.05), after adjusting for Ewing sarcoma diagnosis (HR 5.15; 95% CI 1.55-17.14), metastatic disease at diagnosis (HR 3.88; 95% CI 1.29-11.64), and age (per-year HR 1.04; 95% CI 1.02-1.07). CONCLUSIONS: Limb salvage is oncologically-feasible for calcaneal malignancies.

Development and Internal Validation of Machine Learning Algorithms for Preoperative Survival Prediction of Extremity Metastatic Disease.

BACKGROUND: A preoperative estimation of survival is critical for deciding on the operative management of metastatic bone disease of the extremities. Several tools have been developed for this purpose, but there is room for improvement. Machine learning is an increasingly popular and flexible method of prediction model building based on a data set. It raises some skepticism, however, because of the complex structure of these models. QUESTIONS/PURPOSES: The purposes of this study were (1) to develop machine learning algorithms for 90-day and 1-year survival in patients who received surgical treatment for a bone metastasis of the extremity, and (2) to use these algorithms to identify those clinical factors (demographic, treatment related, or surgical) that are most closely associated with survival after surgery in these patients. METHODS: All 1090 patients who underwent surgical treatment for a long-bone metastasis at two institutions between 1999 and 2017 were included in this retrospective study. The median age of the patients in the cohort was 63 years (interquartile range [IQR] 54 to 72 years), 56% of patients (610 of 1090) were female, and the median BMI was 27 kg/m (IQR 23 to 30 kg/m). The most affected location was the femur (70%), followed by the humerus (22%). The most common primary tumors were breast (24%) and lung (23%). Intramedullary nailing was the most commonly performed type of surgery (58%), followed by endoprosthetic reconstruction (22%), and plate screw fixation (14%). Missing data were imputed using the missForest methods. Features were selected by random forest algorithms, and five different models were developed on the training set (80% of the data): stochastic gradient boosting, random forest, support vector machine, neural network, and penalized logistic regression. These models were chosen as a result of their classification capability in binary datasets. Model performance was assessed on both the training set and the validation set (20% of the data) by discrimination, calibration, and overall performance. RESULTS: We found no differences among the five models for discrimination, with an area under the curve ranging from 0.86 to 0.87. All models were well calibrated, with intercepts ranging from -0.03 to 0.08 and slopes ranging from 1.03 to 1.12. Brier scores ranged from 0.13 to 0.14. The stochastic gradient boosting model was chosen to be deployed as freely available web-based application and explanations on both a global and an individual level were provided. For 90-day survival, the three most important factors associated with poorer survivorship were lower albumin level, higher neutrophil-to-lymphocyte ratio, and rapid growth primary tumor. For 1-year survival, the three most important factors associated with poorer survivorship were lower albumin level, rapid growth primary tumor, and lower hemoglobin level. CONCLUSIONS: Although the final models must be externally validated, the algorithms showed good performance on internal validation. The final models have been incorporated into a freely accessible web application that can be found at https://sorg-apps.shinyapps.io/extremitymetssurvival/. Pending external validation, clinicians may use this tool to predict survival for their individual patients to help in shared treatment decision making. LEVEL OF EVIDENCE: Level III, therapeutic study.

Thirty-day Postoperative Complications After Surgery For Metastatic Long Bone Disease Are Associated With Higher Mortality at 1 Year.

BACKGROUND: The benefits of surgical treatment of a metastasis of the extremities may be offset by drawbacks such as potential postoperative complications. For this group of patients, the primary goal of surgery is to improve quality of life in a palliative setting. A better comprehension of factors associated with complications and the impact of postoperative complications on mortality may prevent negative outcomes and help surgeons in surgical decision-making. QUESTIONS/PURPOSES: (1) What is the risk of 30-day postoperative complications after surgical treatment of osseous metastatic disease of the extremities? (2) What predisposing factors are associated with a higher risk of 30-day complications? (3) Are minor and major 30-day complications associated with higher mortality at 1 year? METHODS: Between 1999 and 2016, 1090 patients with osseous metastatic disease of the long bones treated surgically at our institution were retrospectively included in the study. Surgery included intramedullary nailing (58%), endoprosthetic reconstruction (22%), plate-screw fixation (14%), dynamic hip screw fixation (2%), and combined approaches (4%). Surgery was performed if patients were deemed healthy enough to proceed to surgery and wished to undergo surgery. All data were retrieved by manually reviewing patients' records. The overall frequency of complications, which were defined using the Clavien-Dindo classification system, was calculated. We did not include Grade I complications as postoperative complications and complications were divided into minor (Grade II) and major (Grades III-V) complications. A multivariate logistic regression analysis was used to identify factors associated with 30-day postoperative complications. A Cox regression analysis was used to assess the association between postoperative complications and overall survival. RESULTS: Overall, 31% of the patients (333 of 1090) had a postoperative complication within 30 days. The following factors were independently associated with 30-day postoperative complications: rapidly growing primary tumors classified according to the modified Katagiri classification (odds ratio 1.6; 95% confidence interval, 1.1-2.2; p = 0.011), multiple bone metastases (OR 1.6; 95% CI, 1.1-2.3; p = 0.008), pathologic fracture (OR 1.5; 95% CI, 1.1-2.0; p = 0.010), lower-extremity location (OR 2.2; 95% CI, 1.6-3.2; p < 0.001), hypoalbuminemia (OR 1.7; 95% CI, 1.2-2.4; p = 0.002), hyponatremia (OR 1.5; 95% CI, 1.0-2.2; p = 0.044), and elevated white blood cell count (OR 1.6; 95% CI, 1.1-2.4; p = 0.007). Minor and major postoperative complications within 30 days after surgery were both associated with greater 1-year mortality (hazard ratio 1.6; 95% CI, 1.3-1.8; p < 0.001 and HR 3.4; 95% CI, 2.8-4.2, respectively; p < 0.001). CONCLUSION: Patients with metastatic disease in the long bones are vulnerable to postoperative adverse events. When selecting patients for surgery, surgeons should carefully assess a patient's cancer status, and several preoperative laboratory values should be part of the standard work-up before surgery. Furthermore, 30-day postoperative complications decrease survival within 1 year after surgery. Therefore, patients at a high risk of having postoperative complications are less likely to profit from surgery and should be considered for nonoperative treatment or be monitored closely after surgery. LEVEL OF EVIDENCE: Level III, therapeutic study.

Ambulatory status after surgical and nonsurgical treatment for spinal metastasis.

BACKGROUND: Decisions for operative or nonoperative management remain challenging for patients with spinal metastases, especially when life expectancy and quality of life are not easily predicted. This study evaluated the effects of operative and nonoperative management on maintenance of ambulatory function and survival for patients treated for spinal metastases. METHODS: Propensity matching was used to yield an analytic sample in which operatively and nonoperatively treated patients were similar with respect to key baseline covariates. The study included patients treated for spinal metastases between 2005 and 2017 who were 40 to 80 years old, were independent ambulators at presentation, and had fewer than 5 medical comorbidities. It evaluated the influence of operative care and nonoperative care on ambulatory function 6 months after presentation as the primary outcome. Survival at 6 months and survival at 1 year were secondary outcomes. RESULTS: Nine hundred twenty-nine individuals eligible for inclusion were identified, with 402 (201 operative patients and 201 nonoperative patients) retained after propensity score matching. Patients treated operatively had a lower likelihood than those treated nonoperatively of being nonambulatory 6 months after presentation (3% vs 16%; relative risk [RR], 0.16; 95% confidence interval [CI], 0.06-0.46) as well as a reduced risk of 6-month mortality (20% vs 29%; RR, 0.69; 95% CI, 0.49-0.98). CONCLUSIONS: These results indicate that in a group of patients with similar demographic and clinical characteristics, those treated operatively were less likely to lose ambulatory function 6 months after presentation than those managed nonoperatively. For patients with spinal metastases, our data can be incorporated into discussions about the treatments that align best with patients' preferences regarding surgical risk, mortality, and ambulatory status.

Prognostic value of serum alkaline phosphatase in spinal metastatic disease.

BACKGROUND: Determination of the appropriateness of invasive management in patients with spinal metastatic disease requires accurate pre-operative estimation of survival. The purpose of this study was to examine serum alkaline phosphatase as a prognostic marker in spinal metastatic disease. METHODS: Chart reviews from two tertiary care centres were used to identify spinal metastatic disease patients. Bivariate and multivariate analyses were used to determine if serum alkaline phosphatase was an independent prognostic marker for survival. RESULTS: Overall, 732 patients were included with 90-day and 1-year survival of n = 539 (74.9%) and n = 324 (45.7%), respectively. The 1-year survival of patients in the first quartile of alkaline phosphatase (≤73 IU/L) was 78 (57.8%) compared to 31 (24.0%) for patients in the fourth quartile (>140 IU/L). Preoperative serum alkaline phosphatase levels were significantly elevated in patients with multiple spine metastases, non-spine bone metastasis, and visceral metastasis but not in patients with brain metastasis. On multivariate analysis, elevated serum alkaline phosphatase was identified as an independent prognostic factor for survival in spinal metastatic disease. CONCLUSION: Serum alkaline phosphatase is associated with preoperative metastatic tumour burden and is a biomarker for overall survival in spinal metastatic disease.

High Risk of Symptomatic Venous Thromboembolism After Surgery for Spine Metastatic Bone Lesions: A Retrospective Study.

BACKGROUND: Cancer and spinal surgery are both considered risk factors for venous thromboembolism (VTE). However, the risk of symptomatic VTE for patients undergoing surgery for spine metastases remains undefined. QUESTIONS/PURPOSES: The purposes of this study were to: (1) identify the proportion of patients who develop symptomatic VTE within 90-days of surgical treatment for spine metastases; (2) identify the factors associated with the development of symptomatic VTE among patients receiving surgery for spine metastases; (3) assess the association between the development of postoperative symptomatic VTE and 1-year survival among patients who underwent surgery for spine metastases; and (4) assess if chemoprophylaxis increases the risk of wound complications among patients who underwent surgery for spine metastases. METHODS: Between 2002 and 2014, 637 patients at two hospitals underwent spine surgery for metastases. We considered eligible for analysis adult patients whose procedures were to treat cervical, thoracic, or lumbar metastases (including lymphoma and multiple myeloma). At followup after 90 days and 1 year, respectively, 21 of 637 patients (3%) and 41 of 637 patients (6%) were lost to followup. In general, we used 40 mg of enoxaparin or 5000 IUs subcutaneous heparin every 12 hours. Patients on preoperative chemoprophylaxis continued their initial medication postoperatively. All chemoprophylaxis was started 48 hours after surgery and continued day to day but was discontinued if a bleeding complication developed. Low-molecular-weight heparin (including enoxaparin and dalteparin, in general dosages of respectively 40 mg and 5000 IUs daily) was the most commonly used chemoprophylaxis in 308 patients (48%). Subcutaneous heparin was injected into 127 patients (20%); aspirin was used for 92 patients (14%); and warfarin was administered in 21 patients (3.3%). No form of chemoprophylaxis was prescribed for 89 patients (14%). The primary outcome variable, VTE, was defined as any symptomatic pulmonary embolism (PE) or symptomatic deep venous thromboembolism (DVT) within 90 days of surgery as determined by chart review. The secondary outcome was defined as any documented wound complication within 90 days of surgery that might be attributable to chemoprophylaxis. Statistical analysis was performed using multivariable logistic and Cox regression and Kaplan-Meier. RESULTS: Overall, 72 of 637 patients (11%) had symptomatic VTE; 38 (6%) developed a PE-eight (1.3%) of which were fatal-and 40 (6%) a DVT. After controlling for relevant confounding variables such as age, the modified Charlson Comorbidity Index, visceral metastases, and chemoprophylaxis, longer duration of surgery was independently associated with an increased risk of symptomatic VTE (odds ratio 1.15 for each additional hour of surgery; 95% confidence interval [CI], 1.04-1.28; p = 0.009). After controlling for relevant confounding variables such as age, the modified Charlson Comorbidity Index, visceral metastases, and primary tumor type, patients with symptomatic VTE had a worse 1-year survival rate (VTE, 38%; 95% CI, 27-49 versus nonVTE, 47%; 95% CI, 42-51; p = 0.044). After controlling for relevant confounding variables, no association was found between wound complications and the use of chemoprophylaxis (odds ratio, 1.34; 95% CI, 0.62-2.90; p = 0.459). The overall proportion of patients who developed a wound complication was 10% (66 of 637), including 1.1% (seven of 637) spinal epidural hematomas. CONCLUSIONS: The risk of both symptomatic PE and fatal PE is high in this patient population, and those with symptomatic VTE were less likely to survive 1-year than those who did not, though this may reflect overall infirmity as much as anything else, because many of these patients did not die from VTE-related complications. Further study, such as randomized controlled trials with consistent postoperative VTE screening comparing different chemoprophylaxis regimens, are needed to identify better VTE prevention strategies. LEVEL OF EVIDENCE: Level III, therapeutic study.

Does the SORG Algorithm Predict 5-year Survival in Patients with Chondrosarcoma? An External Validation.

BACKGROUND: We developed a machine learning algorithm to predict the survival of patients with chondrosarcoma. The algorithm demonstrated excellent discrimination and calibration on internal validation in a derivation cohort based on data from the Surveillance, Epidemiology, and End Results (SEER) registry. However, the algorithm has not been validated in an independent external dataset. QUESTIONS/PURPOSES: Does the Skeletal Oncology Research Group (SORG) algorithm accurately predict 5-year survival in an independent patient population surgically treated for chondrosarcoma? METHODS: The SORG algorithm was developed using the SEER registry, which contains demographic data, tumor characteristics, treatment, and outcome values; and includes approximately 30% of the cancer patients in the United States. The SEER registry was ideal for creating the derivation cohort, and consequently the SORG algorithm, because of the high number of eligible patients and the availability of most (explanatory) variables of interest. Between 1992 to 2013, 326 patients were treated surgically for extracranial chondrosarcoma of the bone at two tertiary care referral centers. Of those, 179 were accounted for at a minimum of 5 years after diagnosis in a clinical note at one of the two institutions, unless they died earlier, and were included in the validation cohort. In all, 147 (45%) did not meet the minimum 5 years of followup at the institution and were not included in the validation of the SORG algorithm. The outcome (survival at 5 years) was checked for all 326 patients in the Social Security death index and were included in the supplemental validation cohort, to also ascertain validity for patients with less than 5 years of institutional followup. Variables used in the SORG algorithm to predict 5-year survival including sex, age, histologic subtype, tumor grade, tumor size, tumor extension, and tumor location were collected manually from medical records. The tumor characteristics were collected from the postoperative musculoskeletal pathology report. Predicted probabilities of 5-year survival were calculated for each patient in the validation cohort using the SORG algorithm, followed by an assessment of performance using the same metrics as used for internal validation, namely: discrimination, calibration, and overall performance. Discrimination was calculated using the concordance statistic (or the area under the Receiver Operating Characteristic (ROC) curve) to determine how well the algorithm discriminates between the outcome, which ranges from 0.5 (no better than a coin-toss) to 1.0 (perfect discrimination). Calibration was assessed using the calibration slope and intercept from a calibration plot to measure the agreement between predicted and observed outcomes. A perfect calibration plot should show a 45° upwards line. Overall performance was determined using the Brier score, ranging from 0 (excellent prediction) to 1 (worst prediction). The Brier score was compared with the null-model Brier score, which showed the performance of a model that ignored all the covariates. A Brier score lower than the null model Brier score indicated greater performance of the algorithm. For the external validation an F1-score was added to measure the overall accuracy of the algorithm, which ranges between 0 (total failure of an algorithm) and 1 (perfect algorithm).The 5-year survival was lower in the validation cohort than it was in the derivation cohort from SEER (61.5% [110 of 179] versus 76% [1131 of 1544] ; p < 0.001). This difference was driven by higher proportion of dedifferentiated chondrosarcoma in the institutional population than in the derivation cohort (27% [49 of 179] versus 9% [131 of 1544]; p < 0.001). Patients in the validation cohort also had larger tumor sizes, higher grades, and nonextremity tumor locations than did those in the derivation cohort. These differences between the study groups emphasize that the external validation is performed not only in a different patient cohort, but also in terms of disease characteristics. Five-year survival was not different for both patient groups between subpopulations of patients with conventional chondrosarcomas and those with dedifferentiated chondrosarcomas. RESULTS: The concordance statistic for the validation cohort was 0.87 (95% CI, 0.80-0.91). Evaluation of the algorithm's calibration in the institutional population resulted in a calibration slope of 0.97 (95% CI, 0.68-1.3) and calibration intercept of -0.58 (95% CI, -0.20 to -0.97). Finally, on overall performance, the algorithm had a Brier score of 0.152 compared with a null-model Brier score of 0.237 for a high level of overall performance. The F1-score was 0.836. For the supplementary validation in the total of 326 patients, the SORG algorithm had a validation of 0.89 (95% CI, 0.85-0.93). The calibration slope was 1.13 (95% CI, 0.87-1.39) and the calibration intercept was -0.26 (95% CI, -0.57 to 0.06). The Brier score was 0.11, with a null-model Brier score of 0.19. The F1-score was 0.901. CONCLUSIONS: On external validation, the SORG algorithm retained good discriminative ability and overall performance but overestimated 5-year survival in patients surgically treated for chondrosarcoma. This internet-based tool can help guide patient counseling and shared decision making. LEVEL OF EVIDENCE: Level III, prognostic study.

Amputation for Extremity Sarcoma: Contemporary Indications and Outcomes.

INTRODUCTION: Amputation for localized extremity sarcoma (ES), once the primary therapy, is now rarely performed. We reviewed our experience to determine why patients with sarcoma still undergo immediate or delayed amputation, identify differences based on amputation timing, and evaluate outcomes. METHODS: Records of patients with primary, nonmetastatic ES who underwent amputation at our institution from 2001 to 2011 were reviewed. Univariate analysis was performed, and survival outcomes were calculated. RESULTS: We categorized 54 patients into three cohorts: primary amputation (A1, n = 18, 33%), secondary amputation after prior limb-sparing surgery (A2, n = 22, 41%), and hand and foot sarcomas (HF, n = 14, 26%). Median age at amputation was 54 years (range 18-88 years). Common indications for amputation (> 40%) were loss of function, bone involvement, multiple compartment involvement, and large tumor size (A1); proximal location, joint involvement, neurovascular compromise, multiple compartment involvement, multifocal or fungating tumor, loss of function, and large tumor size (A2); and joint involvement and prior unplanned surgery (HF). There was no difference in disease-specific survival (DSS) (p = 0.19) or metastasis-free survival (MFS) (p = 0.31) between early (A1) and delayed (A2) amputation. Compared with cohorts A1/A2, HF patients had longer overall survival (OS) (p = 0.04). CONCLUSIONS: Indications for amputation for extremity sarcoma vary between those who undergo primary amputation, delayed amputation, and amputation for hand or foot sarcoma. Amputations chosen judiciously are associated with excellent disease control and survival. For patients who ultimately need amputation, timing (early vs. delayed) does not affect survival.

Clinical characteristics and treatment outcomes in six cases of malignant tenosynovial giant cell tumor: initial experience of molecularly targeted therapy.

BACKGROUND: Although tenosynovial giant cell tumor (TGCT) is classified as a benign tumor, it may undergo malignant transformation and metastasize in extremely rare occasions. High aberrant expression of CSF1 has been implicated in the development of TGCT and recent studies have shown promising activity of several CSF1R inhibitors against benign diffuse-type TGCT; however, little is known about their effects in malignant TGCT. CASE PRESENTATION: Information from six consenting patients (3 men, 3 women) with malignant TGCT presenting to Dana-Farber Cancer Institute for initial or subsequent consultation was collected. Median age at initial diagnosis of TGCT was 49.5 years (range 12-55), and median age at diagnosis of malignant TGCT was 50 years (range 34-55). Two patients developed malignant TGCT de novo, while four other cases showed metachronous malignant transformation. All tumors arose in the lower extremities (3 knee, 2 thigh, 1 hip). Five patients underwent surgery for the primary tumors, and four developed local recurrence. All six patients developed lung metastases, and four of five evaluable tumors developed inguinal and pelvic lymph node metastases. All six patients received systemic therapy. Five patients were treated with at least one tyrosine kinase inhibitor with inhibitory activity against CSF1R; however, only one patient showed clinical benefit (SD or PR). Five patients were treated with conventional cytotoxic agents. Doxorubicin-based treatment showed clinical benefit in all four evaluable patients, and gemcitabine/docetaxel showed clinical benefit in two patients. All six patients died of disease after a median of 21.5 months from diagnosis of malignant TGCT. CONCLUSIONS: This study confirms that TGCT may transform into an aggressive malignant tumor. Lymph node and pulmonary metastases are common. Local recurrence rates are exceedingly high. Conventional cytotoxic chemotherapy showed clinical benefit, whereas tyrosine kinase inhibitors against CSF1R showed limited activity. Given its rarity, a prospective registry of malignant TGCT patients is needed to further understand the entity and to develop effective strategies for systemic treatment.

Predicting pathological fracture in femoral metastases using a clinical CT scan based algorithm: A case-control study.

BACKGROUND: We assessed whether there was a difference in attenuation measurements (in Hounsfield units - HU) and geometric distribution of HU between femora with metastatic lesions that fracture, and metastatic lesions that did not fracture nor underwent prophylactic fixation. METHODS: Nine patients with femoral metastases who underwent CT and developed a pathological fracture were matched to controls. All femora were delineated in axial CT slices using a region of interest (ROI) tool; the HU within these ROIs were used to calculate: (1) the cumulative HU of the affected over the nonaffected side per slice and presented as a percentage, and (2) the cumulative HU accounting for geometric distribution (polar moment of HU). We repeated the analyses including cortical bone only (HU of 600 and above). RESULTS: CT-based calculations did not differ between patients with a lesion that fractured and those that did not fracture nor underwent prophylactic fixation when analyzing all tissue. However, when including cortical bone only, the pathological fracture group had a lower cumulative HU value compared to the no fracture and no fixation group for the weakest cross-sectional CT image (pathological fracture group, mean: 71, SD: 23 and no fracture and no prophylactic fixation group, mean: 85, SD: 18, p = 0.042) and the complete lesion analysis (pathological fracture group, mean: 78, SD: 21 and no fracture and no prophylactic fixation group, mean: 92, SD: 15, p = 0.032). CONCLUSION: The demonstrated CT-based algorithms can be useful for predicting pathological fractures in metastatic lesions.

Factors associated with infection after reconstructive shoulder surgery for proximal humerus tumors.

BACKGROUND: The main reconstruction techniques for proximal humerus tumors include osteoarticular allografts (OAs), endoprostheses (EPs), or allograft prosthetic composites (APCs). A common complication is infection, and constructs involving the use of allografts are believed to be at a higher risk of infection. Literature comparing infection rates between different modalities of reconstruction is scarce and underpowered. The study purposes were (1) to determine and compare the prevalence of infection in patients who underwent reconstruction of the proximal humerus including OAs, EPs, and APCs; (2) to identify preoperative, perioperative, and postoperative predictors of infection that might be modifiable; and (3) to present our protocol of treatment in patients with superficial and deep infections. METHODS: We reviewed 150 patients of all ages with proximal humerus tumors treated by an OA, EP, or APC at 2 tertiary institutions. The prevalence of infection for each modality was calculated and compared between groups. We identified potential predictors of infection with stepwise backward multivariate Cox regression analysis. RESULTS: An infection developed in 19 patients (12%): 5 of 45 (11%) in the OA group, 12 of 85 (14%) in the EP group, and 2 of 20 (10%) in the APC group (P = .740). A lower preoperative hemoglobin blood level and low preoperative albumin blood level were independently associated with infection. CONCLUSIONS: We found similar infection rates compared with previously reported series. However, we did not identify a higher infection prevalence in constructs using allografts. Patients with a lower preoperative hemoglobin or albumin level are at higher risk of infection and should undergo optimization before surgery.

Are perioperative allogeneic blood transfusions associated with 90-days infection after operative treatment for bone metastases?

BACKGROUND AND OBJECTIVES: We assessed whether allogeneic blood transfusions were associated with infection-within 90 days-after surgery for bone metastatic disease. Furthermore, we assessed other risk factors associated with infection. METHODS: We included 1,266 patients surgically treated for a bone metastasis at two hospitals between 2002 and 2013. Blood transfusions within 7 days before and after surgery were considered perioperative. RESULTS: We found no independent association between exposure to blood transfusion and infection (odds ratio [OR] 1.02, 95% confidence interval [CI]: 0.76-1.37, P = 0.889), nor a dose-response relationship (OR 1.02, 95%CI: 0.98-1.07, P = 0.245). Older age (OR 1.01, 95%CI: 1.00-1.02, P = 0.035), a higher modified Charlson comorbidity index (OR 1.13, 95%CI: 1.05-1.22, P = 0.002), surgery to the axial skeleton (OR 1.89, 95%CI: 1.42-2.51, P < 0.001), and previous radiotherapy (OR 1.45, 95%CI 1.07-1.96, P = 0.015) were independently associated with infection. CONCLUSIONS: There was no association between allogeneic blood transfusion and infection. We found other risk factors that should be taken into consideration when deciding to operate. J. Surg. Oncol. 2016;114:997-1003. © 2016 Wiley Periodicals, Inc.

A comparison of questionnaires for assessing physical function in patients with lower extremity bone metastases.

OBJECTIVES: To assess, (i) the degree to which the: PROMIS Physical Function Cancer, PROMIS Neuro-QoL Mobility, Toronto Extremity Salvage Score (TESS), Lower Extremity Function Score (LEFS), and Musculoskeletal Tumor Society score (MSTS), measure physical function; (ii) differences in coverage and reliability; and (iii) difference in completion time. METHODS: One hundred of 115 (87%) patients with lower extremity metastases participated in this prospective study. We used exploratory factor analysis-correlating questionnaires with an underlying trait-to assess if questionnaires measure the same. Coverage was assessed by floor and ceiling effect and reliability by the standard error of measurement (SEM). Completion time was compared using the Friedman test. RESULTS: All questionnaires measured the same concept; demonstrated by high correlations (>0.7). Floor effect was absent, while ceiling effect was present in all, but highest for the PROMIS Neuro-QoL Mobility (7%). The SEM was below the threshold-indicating reliability-over a wide range of ability levels for the PROMIS-Physical Function, TESS, and LEFS. Completion time differed between questionnaires (P < 0.001) and was shortest for the PROMIS questionnaires. CONCLUSIONS: The PROMIS Physical Function is the most useful questionnaire. This is due to its reliability over a wide range of ability levels, validity, brevity, and good coverage. J. Surg. Oncol. 2016;114:691-696. © 2016 Wiley Periodicals, Inc.

Metastasectomy, intralesional resection, or stabilization only in the treatment of bone metastases from renal cell carcinoma.

BACKGROUND: The mainstay of treatment for bone metastases from renal cell carcinoma is surgery. We assessed if there was a difference in local recurrence, reoperation, and survival between patients who underwent metastasectomy, intralesional curettage, or stabilization only for renal cell carcinoma metastasis to the appendicular skeleton, and if there was a difference in these outcomes based on margin status. METHODS: This retrospective study included 183 patients; 48% underwent metastasectomy (n = 88, margins: 64 negative; 20 positive; 4 unclear), 30% intralesional curettage (n = 54), and 22% stabilization only (n = 41). RESULTS: The recurrence rate differed and was highest after stabilization only (39%), followed by intralesional curettage (22%), and metastasectomy (12%) (P = 0.003). However, we found no difference in reoperation rate (P = 0.847). Survival was better in patients who underwent metastasectomy (P = 0.020). The recurrence rate was lower in patients who had a negative margin (5%) as compared to those with a positive margin (26%) (P < 0.001). However, we found no difference in reoperation rate (P = 0.97). Negative margins showed better survival (P < 0.001). CONCLUSIONS: Our findings emphasize the importance of obtaining negative margins in patients with a good life expectancy, as lower recurrence rate can be attained at a not significant additional risk for reoperation, with a potential impact on survival. J. Surg. Oncol. 2016;114:237-245. © 2016 Wiley Periodicals, Inc.

Complications after surgery for metastatic humeral lesions.

BACKGROUND: Knowledge of surgical outcome and its predictors helps inform patients and aids in surgical decision-making. We aimed to assess the outcome-reoperation and systemic complication rate-of surgery for humeral metastases, myeloma, or lymphoma. Our null hypothesis was that there are no factors associated with these outcomes. METHODS: We included 295 consecutive patients in this retrospective study: 134 (45%) proximal, 131 (44%) diaphyseal, and 30 (10%) distal impending or pathologic fractures. Proximal lesions were treated by intramedullary nailing (43%, n = 57), prosthesis (34%, n = 46), plate-screw fixation (22%, n = 30), and a combination (n = 1). Diaphyseal lesions were treated by intramedullary nailing (69%, n = 91), plate-screw fixation (30%, n = 39), and a combination (n = 1). Distal lesions were treated by plate-screw fixation (97%, n = 29) and intramedullary nailing (3.3%, n = 1). RESULTS: We found 25 (8.5%) reoperations, and 17 (5.8%) patients had 18 systemic complications: pneumonia (3.7%, n = 11), pulmonary embolism (1.3%, n = 4), sepsis (0.68%, n = 2), and fat embolism (0.34%, n = 1). No factors were independently associated with reoperation. Logistic regression analysis demonstrated that favorable cancer status (i.e., a higher modified Bauer score: odds ratio, 0.48; 95% confidence interval, 0.29-0.80; P = .005) was independently associated with a decreased systemic complication rate. CONCLUSION: Poor cancer status was an independent predictor of postoperative systemic complications. This could help inform the patient and anticipate postoperative problems.

Are Allogeneic Blood Transfusions Associated With Decreased Survival After Surgery for Long-bone Metastatic Fractures?

BACKGROUND: Previous studies have shown that perioperative blood transfusion increases cancer recurrence and decreases patient survival after resection of primary malignancies. The question arises whether this association also exists in patients with already disseminated disease undergoing surgery for metastatic long-bone fractures. PURPOSES: We sought to determine whether perioperative allogeneic blood transfusion is associated with decreased survival after operative treatment of long-bone metastatic fractures after accounting for clinical, laboratory, and treatment factors. Secondarily, we aimed to identify potential factors that are associated with decreased survival. METHODS: We included 789 patients in our retrospective study who underwent surgery at two institutions for a pathologic or impending metastatic long-bone fracture. We used multivariable Cox proportional hazards regression model analysis to assess the relationship of perioperative allogeneic blood transfusion with survival, and accounted for patient age, sex, comorbidities, BMI, tumor type, fracture type and location, presence of other bone and visceral metastases, previous radiotherapy and systemic therapy, preoperative embolization, preoperative hemoglobin level, treatment type, anesthesia time, blood loss, duration of hospital admission, year of surgery, and hospital. RESULTS: Considering transfusion as an "exposure," and comparing patients who received transfusions with those who did not, we found that blood transfusion was not associated with decreased survival after accounting for all explanatory variables (hazard ratio [HR] 1.06; 95% CI, 0.87-1.30; p = 0.57). Evaluating transfusion in terms of dose-response, we found that patients who received more transfusions had lower survival compared with those who had fewer transfusions after accounting for all explanatory variables (HR per unit of blood transfused, 1.07; 95% CI, 1.02-1.12; p = 0.005). We found that age (HR, 1.02; 95% CI, 1.01-1.02; p < 0.001), comorbidity status (HR, 1.06; 95% CI, 1.01-1.10; p = 0.014), duration of hospital stay (HR, 1.02; 95% CI 1.00-1.03; p = 0.021), tumor type (HR, 1.71; 95% CI, 1.44-2.03; p < 0.001), and visceral metastases (HR, 1.59; 95% CI, 1.34-1.88; p < 0.001) were independently associated with survival. CONCLUSION: We found that exposure to perioperative allogeneic blood transfusion does not decrease survival, with the numbers available. However, our sample size might have been insufficient to reveal a small but potentially relevant effect. Our results do suggest a dose-response relationship; patients who received more transfusions had lower survival compared with those with fewer transfusions. Risk of death increased by 7% per unit of blood transfused. LEVEL OF EVIDENCE: Level III, prognostic study.