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Objectives: Metastatic bone disease is estimated to develop in up to 17% of patients with melanoma, compromising skeleton integrity resulting in skeletal-related events (SREs), which impair quality of life and reduce survival. The objective of the study was to investigate (1) the proportion of melanoma patients developing SREs following diagnosis of bone metastasis and (2) the predictors for SREs in this patient cohort., Methods: Four hundred and eighty-one patients with bone metastatic melanoma from two tertiary centers in the United States from 2008 to 2018 were included. The primary outcome was 90-day and 1-year occurrence of a SRE, including pathological fractures of bones, cord compression, hypercalcemia, radiotherapy, and surgery. Fine-Gray regression analysis was performed for overall SREs and pathological fracture, with death as a competing risk., Results: By 1-year, 52% (258/481) of patients experienced SREs, and 28% (137/481) had a pathological fracture. At 90-day, lytic lesions, bone pain, elevated calcium and absolute lymphocyte, and decreased albumin and hemoglobin were associated with higher SRE risk. The same factors, except for decreased hemoglobin, were shown to predict development of SREs at 1-year., Conclusion: The high incidence of SREs and pathological fractures warrants vigilance using the identified factors in this study and preventative measures during clinical oncological care., (© 2024 Wiley Periodicals LLC.)

Background: The ability to predict survival accurately in patients with osseous metastatic disease of the extremities is vital for patient counseling and guiding surgical intervention. We, the Skeletal Oncology Research Group (SORG), previously developed a machine-learning algorithm (MLA) based on data from 1999 to 2016 to predict 90-day and 1-year survival of surgically treated patients with extremity bone metastasis. As treatment regimens for oncology patients continue to evolve, this SORG MLA-driven probability calculator requires temporal reassessment of its accuracy., Question/purpose: Does the SORG-MLA accurately predict 90-day and 1-year survival in patients who receive surgical treatment for a metastatic long-bone lesion in a more recent cohort of patients treated between 2016 and 2020?, Methods: Between 2017 and 2021, we identified 674 patients 18 years and older through the ICD codes for secondary malignant neoplasm of bone and bone marrow and CPT codes for completed pathologic fractures or prophylactic treatment of an impending fracture. We excluded 40% (268 of 674) of patients, including 18% (118) who did not receive surgery; 11% (72) who had metastases in places other than the long bones of the extremities; 3% (23) who received treatment other than intramedullary nailing, endoprosthetic reconstruction, or dynamic hip screw; 3% (23) who underwent revision surgery, 3% (17) in whom there was no tumor, and 2% (15) who were lost to follow-up within 1 year. Temporal validation was performed using data on 406 patients treated surgically for bony metastatic disease of the extremities from 2016 to 2020 at the same two institutions where the MLA was developed. Variables used to predict survival in the SORG algorithm included perioperative laboratory values, tumor characteristics, and general demographics. To assess the models' discrimination, we computed the c-statistic, commonly referred to as the area under the receiver operating characteristic (AUC) curve for binary classification. This value ranged from 0.5 (representing chance-level performance) to 1.0 (indicating excellent discrimination) Generally, an AUC of 0.75 is considered high enough for use in clinical practice. To evaluate the agreement between predicted and observed outcomes, a calibration plot was used, and the calibration slope and intercept were calculated. Perfect calibration would result in a slope of 1 and intercept of 0. For overall performance, the Brier score and null-model Brier score were determined. The Brier score can range from 0 (representing perfect prediction) to 1 (indicating the poorest prediction). Proper interpretation of the Brier score necessitates a comparison with the null-model Brier score, which represents the score for an algorithm that predicts a probability equal to the population prevalence of the outcome for each patient. Finally, a decision curve analysis was conducted to compare the potential net benefit of the algorithm with other decision-support methods, such as treating all or none of the patients. Overall, 90-day and 1-year mortality were lower in the temporal validation cohort than in the development cohort (90 day: 23% versus 28%; p < 0.001, and 1 year: 51% versus 59%; p<0.001)., Results: Overall survival of the patients in the validation cohort improved from 28% mortality at the 90-day timepoint in the cohort on which the model was trained to 23%, and 59% mortality at the 1-year timepoint to 51%. The AUC was 0.78 (95% CI 0.72 to 0.82) for 90-day survival and 0.75 (95% CI 0.70 to 0.79) for 1-year survival, indicating the model could distinguish the two outcomes reasonably. For the 90-day model, the calibration slope was 0.71 (95% CI 0.53 to 0.89), and the intercept was -0.66 (95% CI -0.94 to -0.39), suggesting the predicted risks were overly extreme, and that in general, the risk of the observed outcome was overestimated. For the 1-year model, the calibration slope was 0.73 (95% CI 0.56 to 0.91) and the intercept was -0.67 (95% CI -0.90 to -0.43). With respect to overall performance, the model's Brier scores for the 90-day and 1-year models were 0.16 and 0.22. These scores were higher than the Brier scores of internal validation of the development study (0.13 and 0.14) models, indicating the models' performance has declined over time., Conclusion: The SORG MLA to predict survival after surgical treatment of extremity metastatic disease showed decreased performance on temporal validation. Moreover, in patients undergoing innovative immunotherapy, the possibility of mortality risk was overestimated in varying severity. Clinicians should be aware of this overestimation and discount the prediction of the SORG MLA according to their own experience with this patient population. Generally, these results show that temporal reassessment of these MLA-driven probability calculators is of paramount importance because the predictive performance may decline over time as treatment regimens evolve. The SORG-MLA is available as a freely accessible internet application at https://sorg-apps.shinyapps.io/extremitymetssurvival/ .Level of Evidence Level III, prognostic study., Competing Interests: This study was supported by “Stichting de Drie Lichten,” the Michael van Vloten Fund, the Hendrik-Muller fund, and the Nijbakker Morra foundation from the Netherlands. Each author certifies that there are no funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article related to the author or any immediate family members. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research ® editors and board members are on file with the publication and can be viewed on request., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Association of Bone and Joint Surgeons.)

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., (© 2022 American Cancer Society.)

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., (© 2020 Wiley Periodicals LLC.)

Background: Desmoid tumors of the extremities often present with pain and functional limitation, but treatment can lead to morbidity and recurrence is common. The impact of treatment with respect to traditional "oncologic" metrics (such as recurrence rate) has been studied extensively, with a shift in recent years away from local therapies as first-line management; however, little is known about the association between treatment modality and long-term functional outcomes for patients with this benign disease., Questions/purposes: In a retrospective review of consecutive patients treated at two institutions, we asked: (1) Is event-free survival (EFS) different between patients who undergo local treatment and those who do not for primary as well as for recurrent desmoid tumors? (2) What treatment-related factors are associated with worse Patient-reported Outcomes Measurement Information System (PROMIS) function scores at a minimum of 1 year after treatment?, Methods: Between 1991 and 2017, 102 patients with desmoid tumors of the extremities (excluding those of the hands and feet) were treated at two institutions; of those, 85 patients with 90 tumors were followed clinically for at least 1 year (median [range] 59 months follow-up [12 to 293]) and were included in the present analysis. We attempted to contact all patients for administration of PROMIS function (Physical Function Short Form [SF] 10a and Upper Extremity SF v2.0 7a) and Pain Interference (SF 8a) questionnaires. Complete survey data (minimum 1 year follow-up) were available for 46% (39 of 102) of patients with 40 tumors at a median of 125 months follow-up; only these patients were included in PROMIS data analyses. Though there was no formal institutional treatment algorithm in place during the study period, surgical resection typically was the preferred modality for primary tumors; radiation therapy and systemic treatments (including cytotoxic or hormonal agents earlier in the study period, and tyrosine kinase inhibitors later) were often added for recurrent or very symptomatic disease. We coded treatment for each patient into discrete episodes, each defined by a particular treatment strategy: local treatment only (surgery and/or radiation), systemic treatment only, local plus systemic treatment, or observation; treatment episodes rendered at other institutions (that is, before referral) were not included in the analyses. Treatment failure was defined as recurrence after surgical resection, or clinically significant radiologic and/or symptomatic progression after systemic treatment, and EFS was defined as time from treatment initiation to treatment failure or final follow-up. Episodes of treatment for recurrent tumors were analyzed in a pooled fashion, wherein discrete treatment episodes for patients with multiple recurrences were included separately as independent events. We analyzed 56 primary tumors (54 patients), and 101 discrete treatment episodes for recurrent tumors (88 patients). Kaplan-Meier survival curves were constructed separately for the primary and recurrence cohorts, both comparing EFS among patients who received any local treatment (local treatment and local plus systemic treatment groups) versus those who did not (systemic treatment and observation groups). PROMIS function data were analyzed on the bases of patient- and treatment-specific variables, including the PROMIS Pain Interference score as a potential explanatory variable., Results: Within both the primary and recurrence cohorts, there were no differences between the local treatment, systemic treatment, and local plus systemic treatment groups with respect to gender, age, axillary/hip girdle location, or tumor volume. Among primary tumors, 5-year EFS was 44% (95% CI 24 to 80) for the systemic-only group versus 15% (95% CI 5 to 44) for the local treatment group (p = 0.087). Within the pooled recurrence treatment episode cohort, 5-year EFS after systemic-only treatment was 70% (95% CI 52 to 94) versus 56% among patients receiving any local treatment (95% CI 44 to 70; p = 0.46). PROMIS function scores were lowest among patients who underwent two or more resections (39 versus 51 versus 47 for ≥2, 1, and 0 resections, respectively; p = 0.025); among those who received both surgery and radiation at any point, either concurrently or in separate treatment episodes, as compared with those who did not (39 versus 46; p = 0.047); and among those with higher levels of pain interference (38 versus 47 for pain interference scores > 50 versus < 50; p = 0.006)., Conclusions: Patients treated with local modalities (surgery and/or radiation, with or without additional systemic therapy) did not experience improved EFS as compared with those treated without local modalities; this was the case for both the primary and the recurrent tumor cohorts. However, PROMIS function scores were lowest among patients who underwent two or more surgical interventions and among those treated with surgery and radiation at any time, suggesting that more aggressive local treatment may be associated with poorer long-term functional outcomes. Prospective collection of patient-reported outcomes data at multiple time points will allow for more direct correlations between treatment modality and impact on function and will help to elucidate the ideal management strategy for these benign but often-symptomatic tumors., Level of Evidence: Level III, therapeutic study.

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.

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.

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.

Background: Diagnosing giant cell-rich bone tumors can be challenging on limited biopsies. H3 histone family member 3A (H3F3A) (G34W/V/R/L) mutations are present in the majority of giant cell tumors (GCTs) of bone and H3 histone family member 3B (H3F3B) (K36M) mutations are present in nearly all chondroblastomas, but are absent in histologic mimics. Mutation-specific immunohistochemistry (IHC) is highly specific for GCT and chondroblastoma in surgical excisions. The objective of the current study was to validate H3G34W and H3K36M IHC in the diagnosis of giant cell-rich bone tumors on fine-needle aspiration and core needle biopsy specimens., Methods: IHC was performed using monoclonal antibodies against histone H3.3 G34W and K36M in GCTs of bone (26 cases, including 2 malignant cases), GCT of Paget disease (1 case), chondroblastoma (8 cases), aneurysmal bone cyst (7 cases), and osteosarcoma (13 cases) with available fine-needle aspiration and/or core needle biopsy specimens from 2 institutions. H3F3A and H3F3B Sanger sequencing was performed on all 4 H3G34W IHC-negative GCTs., Results: IHC for H3G34W was positive in 22 of 26 GCTs (85%) and negative in all histologic mimics. IHC for H3K36M was positive in all 8 chondroblastomas and negative in all histologic mimics. IHC results were concordant between biopsy and surgical specimens in 152 of 158 samples (96%). Sequencing identified alternate H3F3A G34L and G34V mutations in 1 IHC-negative GCT each, but no mutation was found in the remaining 2 cases., Conclusions: H3G34W and H3K36M IHC is highly specific for GCT and chondroblastoma, respectively, among giant cell-rich bone tumors, and is useful for confirming the diagnosis in limited biopsies. The presence of alternate H3F3A mutations accounts for the H3G34W IHC negativity in a subset of GCT of bone cases. Cancer Cytopathol 2018. © 2018 American Cancer Society., (© 2018 American Cancer Society.)

Background Context: Assessing quality of life, functional outcome, and pain has become important in assessing the effectiveness of treatment for metastatic spine disease. Many questionnaires are able to measure these outcomes; few are validated in patients with metastatic spine disease. As a result, there is no consensus on the ideal questionnaire to use in these patients., Purpose: Our study aim was to assess whether certain questionnaires measuring quality of life, functional outcome, and pain (1) correlated with each other, (2) measured the construct they claim to measure, (3) had good coverage-floor and ceiling effects, (4) were reliable, and (5) whether there were differences in completion time between them., Design: This is a prospective cross-sectional survey study from three outpatient clinics (two orthopedic oncology clinics and one neurosurgery clinic) from two affiliated tertiary hospital care centers., Patient Sample: We included 100 consecutive patients with metastatic spine disease between July 2014 and February 2016. We excluded non-English-speaking patients., Outcome Measures: The following questionnaires were given in random order: Oswestry Disability Index (ODI) or Neck Disability Index (NDI), Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function, PROMIS Pain Intensity, EuroQol-5 Dimensions (EQ-5D), and the Spine Oncology Study Group Outcome Questionnaire (SOSG-OQ)., Methods: We used exploratory factor analysis-correlating questionnaires with an underlying mathematically derived trait-to assess if questionnaires measured the same concept. Coverage was assessed by floor and ceiling effects, and reliability was assessed by standard error of measurement as a function of ability. Differences in completion times were tested using the Friedman test., Results: Questionnaires measured the construct they were developed for, as demonstrated with high correlations (>0.7) with the underlying trait. A floor effect was present in the PROMIS Pain Intensity (7.0%), ODI or NDI (4.0%), and the PROMIS Physical Function (1.0%) questionnaires. A ceiling effect was present in the EQ-5D questionnaire (6.0%). The SOSG-OQ had no floor or ceiling effect. The PROMIS Physical Function and PROMIS Pain Intensity proved to be the most reliable, whereas the EQ-5D was the least reliable. Completion time differed among questionnaires (p<.001) and was shortest for the PROMIS Pain Intensity (median 24 seconds) and PROMIS Physical Function (median 42 seconds)., Conclusions: In patients with metastatic spine disease, we recommend the SOSG-OQ for measuring quality of life, the PROMIS Physical Function for measuring physical function, and the PROMIS Pain Intensity for measuring pain., (Published by Elsevier Inc.)

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., (Copyright © 2016 Journal of Shoulder and Elbow Surgery Board of Trustees. All rights reserved.)

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., (© 2016 Wiley Periodicals, Inc.)

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., (© 2016 Wiley Periodicals, Inc.)

Background Context: Perioperative allogeneic blood transfusions have been associated with decreased survival after surgical resection of primary and metastatic cancer. Studies investigating this association for patients undergoing resection of bone metastases are scarce and controversial., Purpose: We assessed (1) whether exposure to perioperative allogeneic blood transfusions was associated with decreased survival after surgery for spinal metastases and (2) if there was a dose-response relationship per unit of blood transfused. Additionally, we explored the risk factors associated with survival after surgery for spinal metastases., Study Design/setting: This is a retrospective cohort study from two university medical centers., Patient Sample: There were 649 patients who had operative treatment for metastatic disease of the spine between 2002 and 2014. Patients with lymphoma or multiple myeloma were also included. We excluded patients with a revision procedure, kyphoplasty, vertebroplasty, and radiosurgery alone., Outcome Measures: The outcome measure was survival after surgery. The date of death was obtained from the Social Security Death Index and medical charts., Methods: Blood transfusions within 7 days before and 7 days after surgery were considered perioperative. A multivariate Cox proportional hazard model was used to assess the relationship between allogeneic blood transfusion as exposure versus non-exposure, and subsequently as continuous value; we accounted for clinical, laboratory, and treatment factors., Results: Four hundred fifty-three (70%) patients received perioperative blood transfusions, and the median number of units transfused was 3 (interquartile range: 2-6). Exposure to perioperative blood transfusion was not associated with decreased survival after accounting for all explanatory variables (hazard ratio [HR]: 1.03; 95% confidence interval [CI]: 0.80-1.31; p=.841). Neither did we find a dose-response relationship (HR: 1.01; 95% CI: 0.98-1.04; p=.420). Other factors associated with worse survival were older age, more severe comorbidity status, lower preoperativehemoglobin level, higher white blood cell count, higher calcium level, primary tumor type, previous systemic therapy, poor performance status, presence of lung, liver, or brain metastasis, and surgical approach., Conclusions: Perioperative allogeneic blood transfusions were not associated with decreased survival after surgery for spinal metastases. More liberal transfusion policies might be warranted for patients undergoing surgery for spinal metastasis, although careful consideration is needed as other complications may occur., (Copyright © 2016 Elsevier Inc. All rights reserved.)

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., (© 2016 Wiley Periodicals, Inc.)

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., (Copyright © 2016 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Background Context: Choosing appropriate surgical patients in the setting of spinal metastases can be challenging. Existing scoring systems focus primarily on patient selection or operative techniques. These scores are limited in their capacity to predict postoperative survival., Purpose: The aim was to model survival after spine surgery for metastastic disease., Study Design: This was a retrospective multicenter study., Patient Sample: All patients who had undergone surgery for the treatment of metastatic spinal disease at one of four tertiary care centers between 2007 and 2013 were included., Outcome Measure: The outcome measure was 1-year survival after surgery., Methods: Demographic, medical, oncologic, surgical, and survival data were abstracted from medical records. The effect of predictor variables on survival was evaluated alone and in combination using stepwise logistic regression. Multivariable logistic regression was subsequently used to adjust for confounders. A predictive score was then developed and compared against that of the modified Bauer score alone in terms of prognosticating 1-year survival after surgery., Results: In the time period under investigation, 318 patients underwent surgical intervention for metastastic disease involving the spine, with 307 having data available for analysis. The survival rate at 1 year was 48% (n=142), with a median survival of 10 months. In final adjusted analysis, preoperative modified Bauer score (odds ratio [OR] 3.00; 95% confidence interval [CI] 1.80-5.01; p<.001), ambulatory status (OR 2.47; 95% CI 1.48-4.14; p=.001), and serum albumin (OR 2.80; 95% CI 1.66-4.72; p<.001) were all independent predictors of 1-year survival. The most parsimonious model weighted the modified Bauer score with 2 points and intact ambulatory status and normal serum albumin level with 1 point each, with a ceiling score of 3. The final model using the predictive score was able to explain 74% of the variation in 1-year survival. In contrast, the modified Bauer score alone was only able to explain 64% of the variation in 1-year survival., Conclusions: This study demonstrates the importance of including factors related to the overall health of a patient, in addition to parameters surrounding their cancer diagnosis, to better prognosticate survival. Our predictive score performed better than the modified Bauer alone and may be used to predict survival after surgical intervention for metastatic disease., Level of Evidence: III., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Survival estimation guides surgical decision-making in metastatic bone disease. Traditionally, classic scoring systems, such as the Bauer score, provide survival estimates based on a summary score of prognostic factors. Identification of new factors might improve the accuracy of these models. Additionally, the use of different algorithms--nomograms or boosting algorithms--could further improve accuracy of prognostication relative to classic scoring systems. A nomogram is an extension of a classic scoring system and generates a more-individualized survival probability based on a patient's set of characteristics using a figure. Boosting is a method that automatically trains to classify outcomes by applying classifiers (variables) in a sequential way and subsequently combines them. A boosting algorithm provides survival probabilities based on every possible combination of variables., Questions/purposes: We wished to (1) assess factors independently associated with decreased survival in patients with metastatic long bone fractures and (2) compare the accuracy of a classic scoring system, nomogram, and boosting algorithms in predicting 30-, 90-, and 365-day survival., Methods: We included all 927 patients in our retrospective study who underwent surgery for a metastatic long bone fracture at two institutions between January 1999 and December 2013. We included only the first procedure if patients underwent multiple surgical procedures or had more than one fracture. Median followup was 8 months (interquartile range, 3-25 months); 369 of 412 (90%) patients who where alive at 1 year were still in followup. Multivariable Cox regression analysis was used to identify clinical and laboratory factors independently associated with decreased survival. We created a classic scoring system, nomogram, and boosting algorithms based on identified variables. Accuracy of the algorithms was assessed using area under the curve analysis through fivefold cross validation., Results: The following factors were associated with a decreased likelihood of survival after surgical treatment of a metastatic long bone fracture, after controlling for relevant confounding variables: older age (hazard ratio [HR], 1.0; 95% CI, 1.0-1.0; p < 0.001), additional comorbidity (HR, 1.2; 95% CI, 1.0-1.4; p = 0.034), BMI less than 18.5 kg/m(2) (HR, 2.0; 95% CI, 1.2-3.5; p = 0.011), tumor type with poor prognosis (HR, 1.8; 95% CI, 1.6-2.2; p < 0.001), multiple bone metastases (HR, 1.3; 95% CI, 1.1-1.6; p = 0.008), visceral metastases (HR, 1.6; 95% CI, 1.4-1.9; p < 0.001), and lower hemoglobin level (HR, 0.91; 95% CI, 0.87-0.96; p < 0.001). The survival estimates by the nomogram were moderately accurate for predicting 30-day (area under the curve [AUC], 0.72), 90-day (AUC, 0.75), and 365-day (AUC, 0.73) survival and remained stable after correcting for optimism through fivefold cross validation. Boosting algorithms were better predictors of survival on the training datasets, but decreased to a performance level comparable to the nomogram when applied on testing datasets for 30-day (AUC, 0.69), 90-day (AUC, 0.75), and 365-day (AUC, 0.72) survival prediction. Performance of the classic scoring system was lowest for all prediction periods., Conclusions: Comorbidity status and BMI are newly identified factors associated with decreased survival and should be taken into account when estimating survival. Performance of the boosting algorithms and nomogram were comparable on the testing datasets. However, the nomogram is easier to apply and therefore more useful to aid surgical decision making in clinical practice., Level of Evidence: Level III, prognostic study.

Purpose: To evaluate patterns and predictors of local failure in patients undergoing postoperative radiation therapy (RT) for osseous metastases., Methods and Materials: Patients undergoing postoperative RT for bone metastases between June 2008 and January 2012 were retrospectively reviewed. Patterns of local failure were assessed, and Fine and Gray's univariable and multivariable analyses (MVA) were used to evaluate factors associated with local progression, including dose intensity of RT (biological equivalent dose, BED, Gy10) and percent coverage of the surgical hardware by the RT fields. Additional predictors were similarly assessed, including patient (eg, age, performance status), disease (eg, tumor type, metastasis site), and treatment (eg, interval from surgery to RT) characteristics., Results: A total of 82 cases were followed for a median of 4.3 months (11.5 months among living patients) after treatment completion. Median BED was 39 Gy10 (range, 14-60), and RT fields covered an average of 71% (standard deviation, 26%) of the hardware. Fourteen cases (17%) experienced local progression. Although most (71%) failures occurred within the RT fields, 29% occurred marginally or out of field, but adjacent to surgical hardware. Increasing coverage of the surgical hardware by RT fields was associated with a reduced risk of local failure in MVA (hazard ratio [HR], 0.10; 95% confidence interval [CI], 0.012-0.82; P = .03), whereas a greater risk of failure was seen with increasing time between surgery and RT (HR, 1.03; 95% CI, 1.01-1.06; P = .01). Extremity rather than spinal site trended toward a greater risk of failure but did not reach significance (HR, 3.79; 95% CI, 0.96-14.89; P = .057). BED ≥39 Gy10 did not predict local failure (P = .51) in MVA., Conclusions: Current strategies achieve good outcomes after postoperative RT for osseous metastases. Greater coverage of the surgical hardware with RT fields and avoiding delays between surgery and postoperative RT should be considered to reduce recurrence risk for patients with bone metastases requiring surgical stabilization., (Copyright © 2015 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

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.