Outcomes of Intramedullary Nail Fixation for Metastatic Disease: Impending and Pathologic Fractures.

BACKGROUND/AIM: Intramedullary nail (IMN) fixation has become a treatment mean for impending and pathologic femur fractures. Currently there continues to be a lack of data examining functional outcomes, complications, and survivorship of patients treated with IMNs for metastatic disease of the femur. PATIENTS AND METHODS: We retrospectively identified 183 IMNs placed for impending (n=145) or pathologic (n=38) metastatic fractures from 2010 to 2018. Functional outcomes and complications including blood transfusions, venous thromboembolisms (VTEs) and reoperations were studied. RESULTS: Patients with impending lesions were more likely to be ambulatory at final follow-up (pathologic: 82%, impending: 99%, p<0.0001) and reported greater musculoskeletal tumor society scores (p<0.0001). Likewise, pathologic fractures were associated with greater discharge to non-home locations (p<0.0001) and were more likely to require a postoperative transfusion (pathologic: 66%, impending: 22%, p=0.0001). However, there was no difference in the incidence of VTEs (p=1.00) or reoperations (p=0.69) between cohorts. Patients treated for impending fractures had improved overall survival at 1 year (54% vs. 26%, p<0.0001). CONCLUSION: IMN fixation was durable in impending and pathologic femoral fractures. Early identification of metastases remains critical as patients treated for impending lesions had greater functional outcomes, fewer complications and improved survivorship compared to patients treated for pathologic fractures.

Clinical Outcome Differences in the Treatment of Impending Versus Completed Pathological Long-Bone Fractures.

BACKGROUND: The outcome differences following surgery for an impending versus a completed pathological fracture have not been clearly defined. The purpose of the present study was to assess differences in outcomes following the surgical treatment of impending versus completed pathological fractures in patients with long-bone metastases in terms of (1) 90-day and 1-year survival and (2) intraoperative blood loss, perioperative blood transfusion, anesthesia time, duration of hospitalization, 30-day postoperative systemic complications, and reoperations. METHODS: We retrospectively performed a matched cohort study utilizing a database of 1,064 patients who had undergone operative treatment for 462 impending and 602 completed metastatic long-bone fractures. After matching on 22 variables, including primary tumor, visceral metastases, and surgical treatment, 270 impending pathological fractures were matched to 270 completed pathological fractures. The primary outcome was assessed with the Cox proportional hazard model. The secondary outcomes were assessed with the McNemar test and the Wilcoxon signed-rank test. RESULTS: The 90-day survival rate did not differ between the groups (HR, 1.13 [95% CI, 0.81 to 1.56]; p = 0.48), but the 1-year survival rate was worse for completed pathological fractures (46% versus 38%) (HR, 1.28 [95% CI, 1.02 to 1.61]; p = 0.03). With regard to secondary outcomes, completed pathological fractures were associated with higher intraoperative estimated blood loss (p = 0.03), a higher rate of perioperative blood transfusions (p = 0.01), longer anesthesia time (p = 0.04), and more reoperations (OR, 2.50 [95% CI, 1.92 to 7.86]; p = 0.03); no differences were found in terms of the rate of 30-day postoperative complications or the duration of hospitalization. CONCLUSIONS: Patients undergoing surgery for impending pathological fractures had lower 1-year mortality rates and better secondary outcomes as compared with patients undergoing surgery for completed pathological fractures when accounting for 22 covariates through propensity matching. Patients with an impending pathological fracture appear to benefit from prophylactic stabilization as stabilizing a completed pathological fracture seems to be associated with increased mortality, blood loss, rate of blood transfusions, duration of surgery, and reoperation risk. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Beta-Blocker Therapy Is Associated With Increased 1-Year Survival After Hip Fracture Surgery: A Retrospective Cohort Study.

BACKGROUND: The high mortality rates seen within the first postoperative year after hip fracture surgery have remained relatively unchanged in many countries for the past 15 years. Recent investigations have shown an association between beta-blocker (BB) therapy and a reduction in risk-adjusted mortality within the first 90 days after hip fracture surgery. We hypothesized that preoperative, and continuous postoperative, BB therapy may also be associated with a decrease in mortality within the first year after hip fracture surgery. METHODS: In this retrospective cohort study, all adults who underwent primary emergency hip fracture surgery in Sweden, between January 1, 2008 and December 31, 2017, were included. Patients with pathological fractures and conservatively managed hip fractures were excluded. Patients who filled a prescription within the year before and after surgery were defined as having ongoing BB therapy. The primary outcome of interest was postoperative mortality within the first year. To reduce the effects of confounding from covariates due to nonrandomization in the current study, the inverse probability of treatment weighting (IPTW) method was used. Subsequently, Cox proportional hazards models were fitted to the weighted cohorts. These analyses were repeated while excluding patients who died within the first 30 days postoperatively. This reduces the effect of early deaths due to surgical and anesthesiologic complications as well as the higher degree of advanced directives present in the study population compared to the general population, which allowed for the evaluation of the long-term association between BB therapy and mortality in isolation. Results are reported as hazard ratios (HR) with 95% confidence intervals (CI). Statistical significance was defined as a 2-sided P value <.05. RESULTS: A total of 134,915 cases were included in the study. After IPTW, BB therapy was associated with a 42% reduction the risk of mortality within the first postoperative year (adjusted HR = 0.58, 95% CI, 0.57-0.60; P < .001). After excluding patients who died within the first 30 days postoperatively, BB therapy was associated with a 27% reduction in the risk of mortality (adjusted HR = 0.73, 95% CI, 0.71-0.75; P < .001). CONCLUSIONS: A significant reduction in the risk of mortality in the first year following hip fracture surgery was observed in patients with ongoing BB therapy. Further investigations into this finding are warranted.

Prognostic Importance of Pathological Fractures in Osteosarcomas.

Aims To investigate whether pathological fractures impact on osteosarcoma patient prognosis in Ireland. Methods This was a retrospective study over 22 years in a National Orthopaedic Oncology Centre. There were 117 nonfracture cases and 15 fracture cases. Outcome measures included 5 and 10 year event-free (EFS) and overall survival (OS). Kaplan-Meier curves assessed length of survival and time to death. Results Pathological fracture has no significant effect on 10 year EFS or 10 year OS. 3 factors strongly associate with 10 year OS rates: American Joint Committee on Cancer (AJCC) classification (p<0.001), Metastases site (p<0.001) and Distant recurrence (p<0.001). Fractures had poorer post-chemotherapeutic necrosis rates (p=0.005). Conclusion Pathological fractures have no significant effect on survival rates or length of survival in an Irish population. The effect of pathological fractures on necrosis rates must be explored in future research.

Serum albumin level predicts survival after surgical treatment of metastatic femur fractures: a retrospective study.

BACKGROUND: Surgical treatment for metastatic pathological femur fractures is associated with high mortality. Correct estimation of prognosis helps in determining the palliative value of surgical treatment and informs surgical decision. This study evaluates the risk factors for mortality in these patients who were surgically treated. METHODS: This is a retrospective study of 112 patients with surgical treatment of metastatic pathological femur fractures. Risk factors evaluated included age, ASA status, Charlson comorbidity index, preoperative serum albumin and haemoglobin, primary tumour site, presence of visceral metastases, presence of spinal metastases, time from diagnosis of cancer to occurrence of pathological fracture, type of surgical procedure performed, lesion and whether treatment was received for an actual or impending fracture. A Cox regression model was used to determine if these factors were independent significant factors for survival. RESULTS: Mortality at 2 years after surgical treatment of metastatic femoral fractures was 86%. Cox regression analysis of risk factors revealed that preoperative serum albumin and type primary tumour were independent risk factors for mortality. Presence of visceral metastases was strongly correlated to serum albumin levels. CONCLUSION: Preoperative serum albumin level and primary tumour site are independent risk factors of survival in patients treated for pathological femur fractures. Serum albumin level may be used as a prognostic tool to guide treatment in this cohort of patients with high mortality rates.

External Validation of PATHFx Version 3.0 in Patients Treated Surgically and Nonsurgically for Symptomatic Skeletal Metastases.

BACKGROUND: PATHFx is a clinical decision-support tool based on machine learning capable of estimating the likelihood of survival after surgery for patients with skeletal metastases. The applicability of any machine-learning tool depends not only on successful external validation in unique patient populations but also on remaining relevant as more effective systemic treatments are introduced. With advancements in the treatment of metastatic disease, it is our responsibility to patients to ensure clinical support tools remain contemporary and accurate. QUESTION/PURPOSES: Therefore, we sought to (1) generate updated PATHFx models using recent data from patients treated at one large, urban tertiary referral center and (2) externally validate the models using two contemporary patient populations treated either surgically or nonsurgically with external-beam radiotherapy alone for symptomatic skeletal metastases for symptomatic lesions. METHODS: After obtaining institutional review board approval, we collected data on 208 patients undergoing surgical treatment for pathologic fractures at Memorial Sloan Kettering Cancer Center between 2015 and 2018. These data were combined with the original PATHFx training set (n = 189) to create the final training set (n = 397). We then created six Bayesian belief networks designed to estimate the likelihood of 1-month, 3-month, 6-month, 12-month, 18-month, and 24-month survival after treatment. Bayesian belief analysis is a statistical method that allows data-driven learning to arise from conditional probabilities by exploring relationships between variables to estimate the likelihood of an outcome using observed data. For external validation, we extracted the records of patients treated between 2016 and 2018 from the International Bone Metastasis Registry and records of patients treated nonoperatively with external-beam radiation therapy for symptomatic skeletal metastases from 2012 to 2016 using the Military Health System Data Repository (radiotherapy-only group). From each record, we collected the date of treatment, laboratory values at the time of treatment initiation, demographic data, details of diagnosis, and the date of death. All records reported sufficient follow-up to establish survival (yes/no) at 24-months after treatment. For external validation, we applied the data from each record to the new PATHFx models. We assessed calibration (calibration plots), accuracy (Brier score), discriminatory ability (area under the receiver operating characteristic curve [AUC]). RESULTS: The updated PATHFx version 3.0 models successfully classified survival at each time interval in both external validation sets and demonstrated appropriate discriminatory ability and model calibration. The Bayesian models were reasonably calibrated to the Memorial Sloan Kettering Cancer Center training set. External validation with 197 records from the International Bone Metastasis Registry and 192 records from the Military Health System Data Repository for analysis found Brier scores that were all less than 0.20, with upper bounds of the 95% confidence intervals all less than 0.25, both for the radiotherapy-only and International Bone Metastasis Registry groups. Additionally, AUC estimates were all greater than 0.70, with lower bounds of the 95% CI all greater than 0.68, except for the 1-month radiotherapy-only group. To complete external validation, decision curve analysis demonstrated clinical utility. This means it was better to use the PATHFx models when compared to the default assumption that all or no patients would survive at all time periods except for the 1-month models. We believe the favorable Brier scores (< 0.20) as well as DCA indicate these models are suitable for clinical use. CONCLUSIONS: We successfully updated PATHFx using contemporary data from patients undergoing either surgical or nonsurgical treatment for symptomatic skeletal metastases. These models have been incorporated for clinical use on PATHFx version 3.0 (https://www.pathfx.org). Clinically, external validation suggests it is better to use PATHFx version 3.0 for all time periods except when deciding whether to give radiotherapy to patients with the life expectancy of less than 1 month. This is partly because most patients survived 1-month after treatment. With the advancement of medical technology in treatment and diagnosis for patients with metastatic bone disease, part of our fiduciary responsibility is to the main current clinical support tools. LEVEL OF EVIDENCE: Level III, therapeutic study.

The effect of surgery type on mortality in elderly patients with pertrochanteric femoral fracture: A Korean nationwide cohort study.

BACKGROUND/OBJECTIVE: The purpose of this study is to analyze the effect of surgical methods on mortality and the relative risk of patients who underwent internal fixation (IF) or hemiarthroplasty (HA) after being diagnosed as a pertrochanteric fracture over 65 years old in a Korean nationwide cohort with a single insurance medical system. METHODS: The Korean National Health Insurance Service-Senior cohort (NHIS-Senior, NHIS-2018-2-111) was used in this study. The eligibility criteria for incident hip fracture patients were the following: (1) first-time admission to acute care hospitals (index admission) with pertrochanteric fracture (ICD-10 S721), (2) three years of hip fracture-free period, (3) recipients of typical surgeries including IF, HA, (4) age between 65 and 99. RESULTS: a total of 7223 patients were enrolled in the cohort. There were 1662 patients (23%) in the HA group and 5561 patients (77%) in the IF group. Mortality rates of the IF group and HA group were 13.46 and 17.94 cases per 100 person-years, respectively. In the multivariable-adjusted Cox proportional hazard model, the HA group had 1.22 times more hazard of all-cause mortality than IF group (aHR 1.22, 95% CI 1.13-1.32). In subgroup analysis, aged 65-79 and female patients showed a prominent association between surgery type and mortality (aHR 1.52, 95% CI 1.29-1.79). CONCLUSIONS: In patients with pertrochanter fracture over 65 years, 1.22-fold mortality rate was observed when HA was performed compared to that of IF, and the difference in mortality was particularly prominent within 1-year after surgery.

Clinical and Molecular Analysis of Pathologic Fracture-associated Osteosarcoma: MicroRNA profile Is Different and Correlates with Prognosis.

BACKGROUND: MicroRNAs are small, noncoding RNAs that regulate the expression of posttranslational genes. The presence of some specific microRNAs has been associated with increased risk of both local recurrence and metastasis and worse survival in patients with osteosarcoma. Pathologic fractures in osteosarcoma are considered to be more the manifestation of a neoplasm with a more aggressive biological behavior than the cause itself of worse prognosis. However, this has not been proved at the biological or molecular level. Currently, there has not been a microRNA profiling study of patients who have osteosarcoma with and without pathologic fractures that has described differences in terms of microRNA profiling between these two groups and their correlation with biologic behavior. QUESTIONS/PURPOSES: (1) In patients with osteosarcoma of the extremities, how do the microRNA profiles of those with and without pathologic fractures compare? (2) What relationship do microRNAs have with local recurrence, risk of metastasis, disease-specific survival, and overall survival in osteosarcoma patients with pathologic fractures? METHODS: Between 1994 and 2013, 217 patients were diagnosed and treated at our institution for osteosarcoma of the extremities. Patients were excluded if (1) they underwent oncologic resection of the osteosarcoma at an outside institution (two patients) or (2) they were diagnosed with an extraskeletal osteosarcoma (29 patients) or (3) they had less than 1 year of clinical follow-up and no oncologic outcome (local recurrence, metastasis, or death) (four patients). A total of 182 patients were eligible. Of those, 143 were high-grade osteosarcomas. After evaluation of tumor samples before chemotherapy treatment, a total of 80 consecutive samples were selected for sequencing. Demographic and clinical comparison between the sequenced and non-sequenced patients did not demonstrate any differences, confirming that both groups were comparable. Diagnostic samples from the extremities of 80 patients with high-grade extremity osteosarcomas who had not yet received chemotherapy underwent microRNA sequencing for an ongoing large-scale osteosarcoma genome profiling project at our institution. Six samples were removed after a second look by a musculoskeletal pathologist who verified cellularity and quality of samples to be sequenced, leaving a total of 74 patients. Of these, two samples were removed as they were confirmed to be pelvic tumors in a second check after sequencing. The final study sample was 72 patients (11 patients with pathologic fractures and 61 without). Sequencing data were correlated with fractures and local recurrence, risk of metastasis, disease-specific survival, and overall survival through Kaplan-Meier analyses. RESULTS: Several microRNAs were expressed differently between the two groups. Among the markers with the highest differential expression (edgeR and DESeq algorithms), Hsa-mIR 656-3p, hsa-miR 493-5p, and hsa-miR 381-3p were upregulated in patients with pathologic fractures, whereas hsa-miR 363, hsa-miR 885-5p, and has-miR 20b-5p were downregulated. The highest differential expression fracture and nonfracture-associated microRNA markers also distinguished groups of patients with different metastasis risk, a well as different disease-specific and overall survival. Furthermore, the profile of pathologic fractures demonstrated a higher differential expression for microRNA markers that were previously associated with a higher risk of metastasis and lower survival rates in patients with osteosarcoma. CONCLUSIONS: In patients who have osteosarcoma, the microRNA profiles of those with pathologic fractures are different than of patients without pathologic fractures. The highest differential expression mircroRNA molecules in patients with pathologic fractures predict also higher risk of metastatic disease as well as worse disease-specific survival and overall survival. Furthermore, we found higher differential expression of microRNAs in the pathologic fracture group previously associated with poor prognosis. The higher risk of metastasis and poorer overall survival in patients with pathologic fractures is inherent to tumor aggressive biologic behavior. It is plausible that the fracture itself is not the direct cause of worse prognosis but another manifestation of tumor biologic aggressiveness. Identification of these molecules through liquid biopsies may help to determine which patients may benefit from surgery before fractures occur. The same technology can be applied to identify patterns of response to conventional chemotherapy, assisting in more specific and accurate systemic therapy. LEVEL OF EVIDENCE LEVEL: III, prognostic study.

Prophylactic Versus Postfracture Stabilization for Metastatic Lesions of the Long Bones: A Comparison of 30-day Postoperative Outcomes.

INTRODUCTION: The goals of orthopaedic treatment for most patients with osseous metastases are to control pain, maintain function, and maximize quality of life and time at home. The aim of this study was to determine differences in 30-day postoperative morbidity and mortality between patients who underwent prophylactic versus postfracture stabilization for metastatic lesions of long bones. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was queried for patients who underwent prophylactic fixation (n = 461) or postfracture stabilization (n = 856) for pathologic fractures because of metastatic lesions of long bones from 2006 to 2016. The groups were compared with respect to several potential confounders using Student t, Kruskal-Wallis, and χ tests. Logistic and Poisson regression models (inclusion threshold of P < 0.1) were used to assess the associations of functional status with outcomes. The alpha level was set at 0.05. RESULTS: Prophylactic fixation was associated with a lower risk of major medical complications (odds ratio = 0.64; 95% confidence interval [CI], 0.45 to 0.93; P = 0.02), discharge to a care facility rather than home (odds ratio = 0.48; 95% CI, 0.36 to 0.63; P < 0.01), and lower risk of a longer hospital stay (incidence risk ratio = 0.86; 95% CI, 0.74 to 0.96; P = 0.01) compared with postfracture stabilization. No significant difference was found in the risk of unplanned revision surgery or 30-day postoperative mortality between the two groups. CONCLUSION: Although prevention of pathologic fractures caused by metastatic disease may not always be possible, patients who underwent prophylactic stabilization had a lower risk of major complications within 30 days postoperatively and shorter hospital stays compared with patients who underwent postfracture stabilization. LEVEL OF EVIDENCE: Level IV, retrospective cohort.

Should the Use of Biologic Agents in Patients With Renal and Lung Cancer Affect Our Surgical Management of Femoral Metastases?

BACKGROUND: Biologic agents may prolong survival of patients with certain kidney and lung adenocarcinomas that have metastasized to bone, and patient response to these agents should be considered when choosing between an endoprosthesis and internal fixation for surgical treatment of femoral metastases. QUESTIONS/PURPOSES: Among patients undergoing surgery for femoral metastases of lung or renal cell carcinoma, (1) Does survival differ between patients who receive only cytotoxic chemotherapy and those who either respond or do not respond to biologic therapy? (2) Does postsurgical incidence of local disease progression differ between groups stratified by systemic treatment and response? (3) Does implant survival differ among groups stratified by systemic treatment and response? METHODS: From our institutional longitudinally maintained orthopaedic database, patients were identified by a query initially identifying all patients who carried a diagnosis of renal cell carcinoma or lung carcinoma. Patients who underwent internal fixation or prosthetic reconstruction between 2000 and 2016 for pathologic fracture of the femur and who survived ≥ 1 year after surgery were studied. Patients who received either traditional cytotoxic chemotherapy or a biologic agent were included. Patients were classified as responders or nonresponders to biologic agents based on whether they had clinical and imaging evidence of a response recorded on two consecutive office visits over ≥ 6 months. Endpoints were overall survival from the time of diagnosis, survival after the femoral operation, evidence of disease progression in the femoral operative site, and symptomatic local disease progression for which revision surgery was necessary. Our analysis included 148 patients with renal (n = 26) and lung (n = 122) adenocarcinoma. Fifty-one patients received traditional chemotherapy only. Of 97 patients who received a biologic agent, 41 achieved a response (stabilization/regression of visceral metastases), whereas 56 developed disease progression. We analyzed overall patient survival with the Kaplan-Meier method and used the log-rank test to identify significant differences (p < 0.05) between groups. RESULTS: One-year survival after surgery among patients responsive to biologic therapy was 61% compared with 20% among patients nonresponsive to biologics (p < 0.001) and 10% among those who received chemotherapy only (p < 0.009). With the number of patients we had to study, we could not detect any difference in local progression of femoral disease associated with systemic treatment and response. Radiologic evidence of periimplant local disease progression developed in three (7%) of 41 patients who responded to biologic treatment, two (3%) of 56 patients nonresponsive to biologics, and one (2%) of 51 patients treated with traditional chemotherapy. With the numbers of patients we had, we could not detect a difference in patients who underwent revision. All three patients responsive to biologics who developed local recurrence underwent revision, whereas the two without a response to biologics did not. CONCLUSIONS: Biologic therapy improves the overall longevity of some patients with lung and renal metastases to the femur in whom a visceral disease response occurred. In our limited cohort, we could not demonstrate an implant survival difference between such patients and those with shorter survival who may have had more aggressive disease. However, an increased life expectancy beyond 1 year among patients responsive to biologics may increase risk of mechanical failure of fixation constructs. LEVEL OF EVIDENCE: Level III, therapeutic study.

Functional recovery after surgical stabilization and postoperative radiotherapy due to metastases of long bones.

PURPOSE: To reinvestigate the functional recovery after combined treatment with surgery and postoperative irradiation of complete or impending pathologic fractures of long bones. METHODS: We retrospectively evaluated the results of external beam radiation therapy (EBRT) carried out after 68 orthopedic stabilization procedures (femur, n = 55, 80.8%; humerus, n = 13, 19.2%) for actual or impending pathological fracture of long bone in 61 patients with skeletal metastases. The mean normalized total dose was 34.7 ± 7.8 Gy. Endpoints were patient's functional status (FS; 1 = normal pain free status; 2 = normal use with pain; 3 = significantly limited used; 4 = nonfunctional status), a need for a secondary procedure to the same site and overall survival following surgery. RESULTS: Overall, 75% of patients achieved normal functional status (FS 1-2) within 12 weeks after surgery. Functional recovery in surviving patients reached 93%. Median survival was 17 months (95% confidence interval 13.7-20.2). Secondary surgical intervention at the same location was necessary in 3 patients (4.4%). On multivariate analysis, only general status (p = 0.011) and growing potential of primary tumor (p = 0.049) were associated with achieving normal functional status within 12 weeks after surgery and radiotherapy. The applied radiation schemes demonstrated a comparable impact on functional recovery. CONCLUSIONS: Our results confirm the effectiveness of stabilizing surgery and fractionated postoperative radiotherapy in terms of functional recovery, supporting prior results assessing postsurgical radiotherapy versus follow-up. The patient's general status is a strong prognostic factor for functional recovery. Rapidly growing tumors may hinder achievement of a normal functional status.

Treatment of pathologic fractures of the proximal femur.

BACKGROUND: Metastatic lesions to the proximal femur occur frequently and require special consideration due to the high risk of pathologic fractures. Type of surgery might influence patient survival considering the growing concept of oligometastases. In fact, the use of modular tumor megaprosthesis is increasing in the last decades compared to intramedullary nailing. Aim of this study was to evaluate oncological and functional results of treatment in patients with pathologic or impending fracture of the proximal femur, with patient survival being the primary, complications the secondary, and functional results the tertiary endpoint. METHODS: Between 2016 and 2017, 40 patients with pathologic fracture (29 cases) or impending fracture according to the Mirels score (11 cases) of the proximal femur, were treated in our Institute and prospectively collected. There were 29 females (72.5%) and 11 males (27.5%), with a mean age at diagnosis of the metastasis of 63.6 years (range 35 to 92 years). Patients were treated due to bone metastases (commonly develop from breast cancer) or hematologic malignancies. Considering number of lesions, 17 patients had less than three bone metastases. Surgical procedures included intramedullary nailing (7 patients), conventional endoprosthesis (4 patients) and modular endoprosthetic replacement (29 patients). Adjuvant treatments included chemotherapy (13 cases), radiation therapy (8 cases) or both (15 cases), and selective arterial embolization (6 pre-op). Oncological results were evaluated considering the survival of patients. Functional results were assessed as pain intensity in VAS score and MSTS score. RESULTS: The mean follow-up of patients was 10.2 months (range 6-26.3 years). At the latest evaluation, 23 patients were alive with disease, 3 patients were alive without evidence of disease and 14 patients were dead with disease. There was a significant better survival in patients treated with PFR compared to IMN and EPR groups (p = 0.0080). No differences in term of survival were found comparing impending vs actual pathological fracture and oligo vs multiple metastases. After surgery, all patients experienced improvement in quality of life resulting from reduction in pain. Mean MSTS score was 22.4. The overall complications rate was 22.5%. The most frequent complication was dislocation followed by wound dehiscence and deep infections. CONCLUSION: Modular tumour prosthesis for proximal femur replacement provides good functional outcome, relative low incidence of complications and higher life quality in the medium term. Oncologic results were influenced by type of surgery, biased by the correct indications for resection and nailing. Preoperative general health condition, life expectancy and ambulatory capacity may influence treatment strategy. With the numbers available, the patients with actual pathologic or impending fracture of the proximal femur treated with resection had a significantly higher survival, especially those with metastases from renal carcinoma or multiple myeloma.

Trends in the surgical treatment of pathological fractures of the long bones: based on a questionnaire among members of the Dutch Orthopaedic Society and the European Musculo-Skeletal Oncology Society (EMSOS).

AIMS: The aim of this study was to assess the current trends in the estimation of survival and the preferred forms of treatment of pathological fractures among national and international general and oncological orthopaedic surgeons, and to explore whether improvements in the management of these patients could be identified in this way. MATERIALS AND METHODS: All members of the Dutch Orthopaedic Society (DOS) and the European Musculoskeletal Oncology Society (EMSOS) were invited to complete a web-based questionnaire containing 12 cases. RESULTS: A total of 96 of 948 members of the DOS (10.1%; groups 1 and 2) and 33 of 182 members of the EMSOS (18%; group 3) replied. The estimation of survival was accurate by more than 50% of all three groups, if the expected survival was short (< 3 months) or long (> 12 months). General orthopaedic surgeons preferred using an intramedullary nail for fractures of the humerus and femur, irrespective of the expected survival or the origin of primary tumour or the location of the fracture. Oncological orthopaedic surgeons recommended prosthetic reconstruction in patients with a long expected survival. CONCLUSION: Identifying patients who require centralized care, as opposed to those who can be adequately treated in a regional centre, can improve the management of patients with pathological fractures. This differentiation should be based on the expected survival, the type and extent of the tumour, and the location of the fracture. Cite this article: Bone Joint J 2018;100-B:1392-8.

Predictors of survival after intramedullary nail fixation of completed or impending pathologic femur fractures from metastatic disease.

BACKGROUND: Surgical decision-making can be challenging when treating patients with osseous metastases. Numerous factors, including expected duration of survival, must be considered to ensure optimal operative stabilization of the affected bone. However, life expectancy of patients with metastatic carcinoma is often difficult to estimate. The goal of our study was to assess the associations of various clinical and demographic factors with survival time after intramedullary nail fixation of impending or completed pathologic femur fractures. METHODS: One hundred thirty-eight consecutive patients treated with intramedullary nail fixation for impending or completed pathologic femur fractures between 2005 and 2017 were included in this study. Factors related to patient survival were assessed with Cox multivariate survival analysis. For all analyses, p < 0.05 was considered significant. RESULTS: The median overall postoperative survival time was 8.4 months. Lower hemoglobin concentration (p = 0.001), lower albumin concentration (p = 0.002), and having a group 2 primary cancer (p = 0.001) were associated with shorter survival on multivariate analysis. When considering the subgroup of 88 prophylactically stabilized patients, lower hemoglobin concentration (p = 0.005), lower albumin concentration (p = 0.015), and having a group 2 primary cancer (p = 0.037) were predictive of shorter survival. CONCLUSION: Several factors are associated with shorter survival after intramedullary nail fixation of pathologic femur fractures. These factors should be considered by orthopedic surgeons when educating patients and determining appropriate treatment.

High Risk of Venous Thromboembolism After Surgery for Long Bone Metastases: A Retrospective Study of 682 Patients.

BACKGROUND: Previous studies have shown that venous thromboembolism (VTE) is a complication associated with neoplastic disease and major orthopaedic surgery. However, many potential risk factors remain undefined. QUESTIONS/PURPOSES: (1) What proportion of patients develop symptomatic VTE after surgery for long bone metastases? (2) What factors are associated with the development of symptomatic VTE among patients receiving surgery for long bone metastases? (3) Is there an association between the development of symptomatic VTE and 1-year survival among patients undergoing surgery for long bone metastases? (4) Does chemoprophylaxis increase the risk of wound complications among patients undergoing surgery for long bone metastases? METHODS: A retrospective study identified 682 patients undergoing surgical treatment of long bone metastases between 2002 and 2013 at the Massachusetts General Hospital and Brigham and Women's Hospital. We included patients 18 years of age or older who had a surgical procedure for impending or pathologic metastatic long bone fracture. We considered the humerus, radius, ulna, femur, tibia, and fibula as long bones; metastatic disease was defined as metastases from solid organs, multiple myeloma, or lymphoma. In general, we used 40 mg enoxaparin daily for lower extremity surgery and 325 mg aspirin daily for lower or upper extremity surgery. The primary outcome was a VTE defined as any symptomatic pulmonary embolism (PE) or symptomatic deep vein thrombosis (DVT; proximal and distal) within 90 days of surgery as determined by chart review. The tertiary outcome was defined as any documented wound complication that might be attributable to chemoprophylaxis within 90 days of surgery. At followup after 90 days and 1 year, respectively, 4% (25 of 682) and 8% (53 of 682) were lost to followup. Statistical analysis was performed using multivariable logistic and Cox regression and Kaplan-Meier. RESULTS: Overall, 6% (44 of 682) of patients had symptomatic VTE; 22 patients sustained a DVT, and 22 developed a PE. After controlling for relevant confounding variables, higher preoperative hemoglobin level was independently associated (odds ratio [OR], 0.75; 95% confidence interval [CI], 0.60-0.93; p = 0.011) with decreased symptomatic VTE risk, the presence of symptomatic VTE was associated with a worse 1-year survival rate (VTE: 27% [95% CI, 14%-40%] and non-VTE: 39% [95% CI, 35%-43%]; p = 0.041), and no association was found between wound complications and the use of chemoprophylaxis (OR, 3.29; 95% CI, 0.43-25.17; p = 0.252). CONCLUSIONS: The risk of symptomatic 90-day VTE is high in patients undergoing surgery for long bone metastases. Further study would be needed to determine the VTE prevention strategy that best balances risks and benefits to address this complication. LEVEL OF EVIDENCE: Level III, therapeutic study.

External Validation and Optimization of the SPRING Model for Prediction of Survival After Surgical Treatment of Bone Metastases of the Extremities.

BACKGROUND: Survival predictions before surgery for metastatic bone disease in the extremities (based on statistical models and data of previous patients) are important for choosing an implant that will function for the remainder of the patient's life. The 2008-SPRING model, presented in 2016, enables the clinician to predict expected survival before surgery for metastatic bone disease in the extremities. However, to maximize the model's accuracy, it is necessary to maintain and update the patient database to refit the prediction models achieving more accurate calibration. QUESTIONS/PURPOSES: The purposes of this study were (1) to refit the 2008-SPRING model for prediction of survival before surgery for metastatic bone disease in the extremities with a more modern cohort; and (2) to evaluate the performance of the refitted SPRING model in a population-based cohort of patients having surgery for metastatic bone disease in the extremities. METHODS: We produced the 2013-SPRING model by adding to the 2008-SPRING model (n = 130) a cohort of patients from a consecutive institutional database of patients who underwent surgery for bone metastases in the extremities with bone resection and reconstruction between 2009 and 2013 at a highly specialized surgical center in Denmark (n = 140). Currently the model is only available as the nomogram fully available in the current article, which is sufficient to use in daily clinical work, but we are working on making the tool available online. As such, the 2013-SPRING model was produced using a consecutive cohort of patients (n = 270) treated during an 11-year period (2003-2013) called the training cohort, all treated with bone resection and reconstruction. We externally validated the 2008-SPRING and the 2013-SPRING models in a prospective cohort (n = 164) of patients who underwent surgery for metastatic bone disease in the extremities from May 2014 to May 2016, called the validation cohort. The validation cohort was identified from a cross-section of the Danish population who were treated for metastatic lesions (using endoprostheses and internal fixation) in the extremities at five secondary surgical centers and one highly specialized surgical center. This cross-section is representative of the Danish population and no patients were treated outside the included centers as a result of public healthcare settings. The indications for surgery for training and the validation cohort were pathologic fracture, impending fracture, or intractable pain despite radiation. Exact date of death was known for all patients as a result of the Danish Civil Registration System and no loss to followup existed. In the training cohort, 150 patients (out of 270 [56%]) and in the validation cohort 97 patients (out of 164 [59%]) died of disease within 1 year postoperatively. The 2013 model did not differ from the 2008 model and included hemoglobin, complete fracture/impending fracture, visceral and multiple bone metastases, Karnofsky Performance Status, and the American Society of Anesthesiologists score and primary cancer. The models were evaluated by area under the receiver operating characteristic curve (AUC ROC) and Brier score (the lower the better). RESULTS: The 2013-SPRING model was successfully refitted with a cohort using more patients than the 2008-SPRING model. Comparison of performance in external validation between the 2008 and 2013-SPRING models showed the AUC ROC was increased by 3% (95% confidence interval [CI], 0%-5%; p = 0.027) and 2% (95% CI, 0%-4%; p = 0.013) at 3-month and 6-month survival predictions, respectively, but not at 12 months at 1% (95% CI, 0%-3%; p = 0.112). Brier score was improved by -0.018 (95% CI, -0.032 to -0.004; p = 0.011) for 3-month, -0.028 (95% CI, -0.043 to -0.0123; p < 0.001) for 6-month, and -0.014 (95% CI, -0.025 to -0.002; p = 0.017) for 12-month survival prediction. CONCLUSIONS: We improved the SPRING model's ability to predict survival after surgery for metastatic bone disease in the extremities. As such, the refitted 2013-SPRING model gives the surgeon a tool to assist in the decision-making of a surgical implant that will serve the patient for the remainder of their life. The 2013-SPRING model may provide increased quality of life for patients with bone metastasis because potential implant failures can be minimized by precise survival prediction preoperatively and the model is freely available and ready to use from the current article. LEVEL OF EVIDENCE: Level I, diagnostic study.

Surgical treatment in bone metastases in the appendicular skeleton. / Tratamiento quirúrgico de las metástasis óseas en el esqueleto apendicular.

INTRODUCTION: Metastatic bone disease is the most common neoplastic process that affects the skeletal system. Eighty percent of bone metastases come from carcinomas of the breast, lung, kidney, thyroid and prostate. The Katagiri scale enables an estimation of the survival of patients based on the presence or absence of visceral metastases, multiple bone metastases and functional status according to the ECOG scale. MATERIAL AND METHODS: A retrospective, descriptive and observational study conducted between March 1, 2013 and June 30, 2015. Thirty-two patients were studied with a diagnosis of metastatic bone disease and who had undergone some type of orthopaedic surgical treatment for pathological fracture or impending fracture. RESULTS: 28 cases (87.5%) presented pathological fracture and 4 cases (12.5%) impending fracture according to the Mirels score. Fifteen cases (46.875%) were treated by placing a central medullary nail + spacer in the long bone diaphysis, 15 cases (46.875%) with modular arthroplasties and 2 patients (6.25%) with forequarter amputation. Eleven patients (34.375%) died during the course of this study, all with a Katagiri greater than or equal to 4. DISCUSSION: The presence of a fracture in previously damaged territory is a catastrophic complication for most cancer patients. A clear understanding of the life expectancy of patients with bone metastases is of great help to prevent errors and failures in treatment.

Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study.

BACKGROUND: Multiple myeloma is characterised by monoclonal paraprotein production and osteolytic lesions, commonly leading to skeletal-related events (spinal cord compression, pathological fracture, or surgery or radiotherapy to affected bone). Denosumab, a monoclonal antibody targeting RANKL, reduces skeletal-related events associated with bone lesions or metastases in patients with advanced solid tumours. This study aimed to assess the efficacy and safety of denosumab compared with zoledronic acid for the prevention of skeletal-related events in patients with newly diagnosed multiple myeloma. METHODS: In this international, double-blind, double-dummy, randomised, active-controlled, phase 3 study, patients in 259 centres and 29 countries aged 18 years or older with symptomatic newly diagnosed multiple myeloma who had at least one documented lytic bone lesion were randomly assigned (1:1; centrally, by interactive voice response system using a fixed stratified permuted block randomisation list with a block size of four) to subcutaneous denosumab 120 mg plus intravenous placebo every 4 weeks or intravenous zoledronic acid 4 mg plus subcutaneous placebo every 4 weeks (both groups also received investigators' choice of first-line antimyeloma therapy). Stratification was by intent to undergo autologous transplantation, antimyeloma therapy, International Staging System stage, previous skeletal-related events, and region. The clinical study team and patients were masked to treatment assignments. The primary endpoint was non-inferiority of denosumab to zoledronic acid with respect to time to first skeletal-related event in the full analysis set (all randomly assigned patients). All safety endpoints were analysed in the safety analysis set, which includes all randomly assigned patients who received at least one dose of active study drug. This study is registered with ClinicalTrials.gov, number NCT01345019. FINDINGS: From May 17, 2012, to March 29, 2016, we enrolled 1718 patients and randomly assigned 859 to each treatment group. The study met the primary endpoint; denosumab was non-inferior to zoledronic acid for time to first skeletal-related event (hazard ratio 0·98, 95% CI 0·85-1·14; pnon-inferiority=0·010). 1702 patients received at least one dose of the investigational drug and were included in the safety analysis (850 patients receiving denosumab and 852 receiving zoledronic acid). The most common grade 3 or worse treatment-emergent adverse events for denosumab and zoledronic acid were neutropenia (126 [15%] vs 125 [15%]), thrombocytopenia (120 [14%] vs 103 [12%]), anaemia (100 [12%] vs 85 [10%]), febrile neutropenia (96 [11%] vs 87 [10%]), and pneumonia (65 [8%] vs 70 [8%]). Renal toxicity was reported in 85 (10%) patients in the denosumab group versus 146 (17%) in the zoledronic acid group; hypocalcaemia adverse events were reported in 144 (17%) versus 106 (12%). Incidence of osteonecrosis of the jaw was not significantly different between the denosumab and zoledronic acid groups (35 [4%] vs 24 [3%]; p=0·147). The most common serious adverse event for both treatment groups was pneumonia (71 [8%] vs 69 [8%]). One patient in the zoledronic acid group died of cardiac arrest that was deemed treatment-related. INTERPRETATION: In patients with newly diagnosed multiple myeloma, denosumab was non-inferior to zoledronic acid for time to skeletal-related events. The results from this study suggest denosumab could be an additional option for the standard of care for patients with multiple myeloma with bone disease. FUNDING: Amgen.

What Factors Are Associated With Early Mortality in Patients Undergoing Femur Surgery for Metastatic Lung Cancer?

BACKGROUND: Pathologic fractures of the femur resulting from metastasis severely increase mortality in patients with nonsmall cell lung cancer (NSCLC). However, factors associated with early mortality after surgery have not been elucidated. QUESTIONS/PURPOSES: The purpose of this study was to identify clinical and laboratory factors available to surgeons before surgery for a metastatic femur in patients with metastatic lung cancer that might be associated with mortality at 1 and 3 months. METHODS: Between 2010 and 2014 we treated 126 patients for pathologic fracture of the femur caused by NSCLC. Of those, complete data sets for the parameters of interest (including clinical factors, laboratory factors, and survivorship) were available in 105 (83%). The factors we considered included sex, age, fracture location, surgical procedure, postoperative complications, blood cell counts, serum biomarkers, genetic alterations of primary cancer, chemotherapeutic agents, preoperative radiation therapy, pleural effusion, bone and internal organ metastasis, performance scores, and medical center where the treatment was performed. Multivariate logistic regression was performed to identify factors associated with mortality at 1 and 3 months. RESULTS: Intertrochanteric location was associated with a higher risk of death (odds ratio [OR], 17.0; 95% confidence interval [CI], 2.65-109.5), lower serum albumin level was associated with an increased risk of death (OR, 0.13; 95% CI, 0.028-0.60), and availability of a suitable chemotherapeutic target agent was associated with a lower risk of death (OR, 0.28; 95% CI, 0.08-0.91) within 3 months of surgery. Undergoing reconstruction with an endoprosthesis was associated with a higher risk of death (OR, 48.3; 95% CI, 1.7-1329) and elevated serum leukocyte count (OR, 1.2; 95% CI, 1.0-1.4) and elevated alanine aminotransferase (ALT) were associated with a higher risk of death (OR, 1.1; 95% CI, 1.0-1.2) within 1 month of surgery. CONCLUSIONS: Although the risk factors for early mortality need to be validated by prospective studies, surgical options need to be reconsidered in patients with femoral metastases from NSCLS showing high ALT or leukocytosis on the preoperative blood test. LEVEL OF EVIDENCE: Level III, prognostic study.

[Bone Metastases - Pathophysiology, Diagnostic Testing and Therapy (Part 1)]. / Knochenmetastasen ­ Pathophysiologie, Diagnostik und Therapie (Teil 1).

In Germany and other European countries, cancer is the second most common cause of death after cardiovascular disease. Although 5-year survival rates for several types of cancer have significantly improved over the last 30 years, metastasis to the bone almost always leads to incurable disease. Aside from the rare primary bone tumours, the treatment of bone metastases now accounts for a major part of tumour orthopaedic workload and requires close interdisciplinary coordination between specialists in oncology, radiology and the discipline of the primary tumour entity. Due to improvements in oncological treatment regimes, long survival times can be achieved. Therefore, the management of so-called "SRE" (skeletal-related events) has gained importance, even in palliative situations. On the basis of a selective literature review, the following article points out the underlying pathophysiological processes of bone metastases and outlines different diagnostic approaches and their relevance in the current clinical setting.