The Role of En Bloc Resection in the Modern Era for Primary Spine Tumors.

STUDY DESIGN: A literature review. OBJECTIVE: The aim of this review is to provide an overview of benign and malignant primary spine tumors and a balanced analysis of the benefits and limitations of (and alternatives to) surgical treatment with en bloc resection. SUMMARY OF BACKGROUND DATA: Primary spine tumors are rare but have the potential to cause severe morbidity, either from the disease itself or as a result of treatment. The prognosis, goals, and treatment options vary significantly with the specific disease entity. Appropriate initial management is critical; inappropriate surgery before definitive treatment can lead to recurrence and may render the patient incurable, as salvage options are often inferior. METHODS: We performed a comprehensive search of the PubMed database for articles relevant to primary spine neoplasms and en bloc spine surgery. Institutional review board approval was not needed. RESULTS: Although Enneking-appropriate en bloc surgery can be highly morbid, it often provides the greatest chance for local control and/or patient survival. However, there is growing data to support modern radiotherapy as a feasible and less morbid approach to certain primary neoplasms that historically were considered radioresistant. CONCLUSIONS: Choosing the optimal approach to primary spine tumors is complex. A comprehensive and up-to-date assessment of the evidence is required to guide patient care and to balance the often-competing goals of prolonging life and preserving quality of life.

Distinct IDH1/2-associated Methylation Profile and Enrichment of TP53 and TERT Mutations Distinguish Dedifferentiated Chondrosarcoma from Conventional Chondrosarcoma.

Dedifferentiated chondrosarcoma (DDCS) is a rare high-grade chondrosarcoma characterized by a well-differentiated chondrosarcoma (WDCS) component that abruptly transitions to a high-grade, noncartilaginous sarcomatous component. To date, the molecular pathogenesis of DDCS and its distinction from conventional chondrosarcoma remain poorly understood. By targeted sequencing, we examined the mutational and copy-number profiles of 18 DDCS, including macrodissected WDCS components, compared with 55 clinically sequenced conventional chondrosarcomas. In conjunction with publicly available external data, we analyzed the methylation and expression profiles of 34 DDCS and 94 conventional chondrosarcomas. Isocitrate dehydrogenase 1/isocitrate dehydrogenase 2 (IDH1/IDH2) mutations were present in 36% conventional chondrosarcomas and 71% DDCS. Compared with conventional chondrosarcomas, DDCS had higher frequencies of TP53 and TERT promoter mutations and CDKN2A/B copy-number losses. Paired analysis of macrodissected WDCS and the high-grade components revealed TERT promoter mutations as early events. Despite phenotypic similarities, the percentage of genome with copy-number alterations in DDCS was significantly lower than that in other high-grade sarcomas. Differential methylation analysis revealed reduction of IDH1/IDH2-associated global hypermethylation characteristically seen in conventional chondrosarcoma and a distinct methylation profile in DDCS. The WDCS and high-grade components in DDCS showed similar methylation profiles. These CpG sites were associated with upregulated expression of genes involved in G2-M checkpoints and E2F targets. Genomic profiling revealed enrichment of TP53, TERT promoter, and CDKN2A/B alterations in DDCS. Integrated methylation and gene expression analysis revealed distinct IDH1/IDH2-associated methylation and transcriptional profiles as early events in DDCS, which may underlie the pathogenesis of dedifferentiation in chondrosarcomas. Significance: DDCS is a rare, high-grade chondrosarcoma with a dismal prognosis. About 50%-80% of DDCS harbor IDH1/IDH2 mutations. We uncover a significant alteration of IDH-associated methylation profile in DDCS, which we propose is key to the progression to dedifferentiation. In this context, the potential effect of the use of IDH inhibitors is unclear but important to address, as clinical trials of selective IDH1 inhibitors showed worse outcome in DDCS.

Fifty years of bone tumors.

There have been enormous advances in the treatment of bone tumors over the past half-century. The most notable of these has been the transition from amputation as the standard of care to limb salvage surgery. This transition is the result of advances in imaging techniques, accurate diagnosis, systemic therapies (including chemotherapy), and prosthetic design for the reconstruction of musculoskeletal defects. Advances have also been made in the management of benign and metastatic bone tumors.

Quantitative preoperative patient assessments are related to survival and procedure outcome for osseous metastases.

Aims: Our objective was to determine if preoperative patient-reported assessments are associated with survival after surgery for stabilization of skeletal metastases. Patients and Methods: All patients with metastatic cancer to bone and indications for skeletal stabilization surgery were approached to participate in a prospective cohort study at a tertiary care center from 2012 to 2017. Of the 208 patients who were eligible, 195 (94%) completed the 36-item Short Form Health Survey (SF-36) preoperatively and underwent surgical treatment of skeletal metastases with complete or impending fractures; the sample encompassed a range of cancer diagnoses and included cases of both internal fixation and endoprosthetic replacement. Cox proportional hazards models were used to identify associations between SF-36 scores and survival. Results: In a model adjusted for clinical factors, patients' mental and physical SF-36 component summary scores were significantly associated with survival, as was their SF-36 composite score (P = 0.004, P = 0.015, and P < 0.001, respectively). Scores in the general health, vitality, and mental health domains were each strongly associated with survival (P < 0.001). Conclusions: Patients' preoperative assessments of their health status are associated with their survival after surgery for skeletal metastases. Patient-reported assessments have the potential to contribute unique information to models that estimate patient survival, as part of efforts to provide optimal, individualized care and make informed decisions about the type and magnitude of surgery for metastatic bone disease that will last the patient's lifetime.

Long-term competing risks for overall and cause-specific failure of rotating-hinge distal femoral arthroplasty for tumour reconstruction.

AIMS: Rotating-hinge knee prostheses are commonly used to reconstruct the distal femur after resection of a tumour, despite the projected long-term burden of reoperation due to complications. Few studies have examined the factors that influence their failure and none, to our knowledge, have used competing risk models to do so. The purpose of this study was to determine the risk factors for failure of a rotating-hinge knee distal femoral arthroplasty using the Fine-Gray competing risk model. METHODS: We retrospectively reviewed 209 consecutive patients who, between 1991 and 2016, had undergone resection of the distal femur for tumour and reconstruction using a rotating-hinge knee prosthesis. The study endpoint was failure of the prosthesis, defined as removal of the femoral component, the tibial component, or the bone-implant fixation; major revision (exchange of the femoral component, tibial component, or the bone-implant fixation); or amputation. RESULTS: Multivariate Fine-Gray regression analyses revealed different hazards for each Henderson failure mode: percentage of femoral resection (p = 0.001) and extent of quadriceps muscle resection (p = 0.005) for overall prosthetic failure; extent of quadriceps muscle resection (p = 0.002) and fixation of femoral component (p = 0.011) for type 2 failure (aseptic loosening); age (p = 0.009) and percentage of femoral resection (p = 0.019) for type 3 failure (mechanical failure); and type of joint resection (p = 0.037) for type 4 (infection) were independent predictors. A bone stem ratio of > 2.5 reliably predicted aseptic loosening. CONCLUSION: We identified independent risk factors for overall and cause-specific prosthetic failure after rotating-hinge knee distal femoral arthroplasty using a competing risk Fine-Gray model. A bone stem ratio > 2.5 reliably predicts aseptic loosening. An accurate knowledge of the risks of distal femoral arthroplasty after resection for tumour assists surgical planning and managing patient expectations. Cite this article: Bone Joint J 2021;103-B(8):1405-1413.

Postoperative extremity compartment syndrome in a cancer center: Incidence and risk factors.

OBJECTIVE: Postoperative compartment syndrome is a reported complication with known patient- and treatment-specific risk factors. Cancer patients carry unique risk factors associated with their underlying disease and long, complex procedures. While elevated serum lactate in traumatic and intensive care settings portends higher risk, no laboratory parameter has demonstrated utility in postoperative risk stratification. Postoperative extremity compartment syndrome in the study institution's cancer population was examined and whether intraoperative serum lactate correlates with postoperative compartment syndrome risk was investigated. METHODS: A 1:2 case-control study was performed, which compared cancer patients with postoperative compartment syndrome to those who underwent similar surgical procedures without this complication. Twelve patients were matched to 24 controls by sex, age, surgical procedures, and duration of surgery. Patient and operative variables were analyzed for prognostic significance. RESULTS: The compartment syndrome rate was 0.09% of all cases (n = 13,491); 0.12% of cases ≥ 3 h' duration (n = 9,979), and 0.25% of cases ≥ 5 h (n = 4,811). Compared with controls, the case group had higher median BMI (31.7 kg/m2 vs. 25.4 kg/m2, P = 0.001), and median intraoperative lactate level (4.05 mmol/L vs. 1.5 mmol/L, P = 0.047). CONCLUSION: Our institutional incidence of postoperative compartment syndrome was similar to that of non-oncologic institutions. While many traditional risk factors did not prove to be influential in our patients, elevated median body mass index and intraoperative serum lactate were identified as risk factors for postoperative compartment syndrome in a cancer population.

Minimal clinically important differences in SF-36 global score: Current value in orthopedic oncology.

The SF-36 is widely used to evaluate the health-related quality of life (HRQoL) of patients with musculoskeletal tumors. Instead of typical methods, calculating the SF-36 Global Score has recently become an increasingly common reporting approach. However, numerical changes lack clear clinical relevance. The minimal clinically important difference (MCID) is useful for interpreting changes in functional scores by defining the smallest change patients may perceive as clinically meaningful. The aim of this study is to determine the MCID of the SF-36 Global Score in orthopedic oncology patients, which has not been reported to date. Three-hundred ten patients who underwent surgery and completed two surveys during postoperative follow-up were reviewed. The two most common methods for calculating the SF-36 Global Score were used: (1) anchor-based methods and receiver operating characteristic analysis based on one-half of the SD of change score and standard error of measurement at baseline and; (2) distribution-based methods. Using anchor-based methods, the MCIDs of SF-36 Global Scores #1 and #2 were 2.7 (area under the curve [AUC] = 0.85) and 2.5 (AUC = 0.79) for improvement, and -1.5 (AUC = 0.81) and -0.6 (AUC = 0.83) for deterioration, respectively. Using distribution-based methods, the MCIDs of SF-36 Global Scores #1 and #2 were 4.1 and 4.4 by half SD, and 4.1 and 4.5 by standard error of measurement, respectively. Our findings provide benchmark values, which can serve as a reference for future studies in musculoskeletal tumor patients using the SF-36 Global Score as a single measure for HRQoL.

The critical difference in the DASH (Disabilities of the Arm, Shoulder, and Hand) outcome measure after essential upper extremity tumor surgery.

BACKGROUND: The DASH (Disabilities of the Arm, Shoulder, and Hand) is a scored questionnaire that is widely used to evaluate the health-related quality of life of patients with upper limb musculoskeletal disorders. However, numerical changes in the measure scores lack clinical significance without meaningful threshold change values of outcome measures that are diagnostically specific. The minimal clinically important difference (MCID) is useful for the interpretation of scores by defining the smallest change that a patient would perceive. However, the MCIDs of the scores in orthopedic oncology patients has not been reported. We aimed to determine the MCIDs of the measure in orthopedic oncology patients. METHODS: Data from our health-related quality of life database from 1999 to 2005 were retrospectively reviewed after institutional review board approval. Seventy-eight patients who underwent surgery and completed 2 surveys during postoperative follow-up were evaluated. Two different methods were used to estimate the MCIDs: distribution-based and anchor-based approaches (the latter used receiver operating characteristic analysis). RESULTS: Using distribution-based methods, the MCIDs of the DASH questionnaire were 7.4 and 8.3 by half standard deviation and the 90% interval of minimal detectable change, respectively. By anchor-based method (receiver operating characteristic analysis), the MCID was 8.3. CONCLUSION: The MCID values calculated by each method validates that the results for upper extremity oncology patients were similar to those reported in other orthopedic conditions. These results identify the threshold for meaningful improvements in DASH scores in orthopedic oncology patients and establish the reference to evaluate health-related quality of life and the outcomes of upper extremity oncology surgery. These data should be further refined for disease- and reconstruction-specific analyses.

Finn/Orthopaedic Salvage System Distal Femoral Rotating-Hinge Megaprostheses in Oncologic Patients: Long-Term Complications, Reoperations, and Amputations.

BACKGROUND: There is a lack of evidence regarding long-term outcomes of rotating-hinge knee prostheses with distal femoral replacement in a large oncologic patient series. In this study, we investigated the proportion of patients experiencing complications requiring surgery in the long term, as well as the cumulative incidence of implant removal/revision and amputation at 5, 10, 15, and 20 years through competing risk analyses. METHODS: We retrospectively studied 214 patients treated with a Finn/Orthopaedic Salvage System (OSS) knee prosthesis (Zimmer Biomet) after distal femoral resection from 1991 to 2017. The study end points were postoperative complications requiring surgery. Reoperations were classified as major when there was (1) removal of the metal-body femoral component, the tibial component, or the bone-implant fixation; (2) major revision (exchange of the metal-body femoral component, the tibial component, or the bone-implant fixation); or (3) amputation. Minor reoperations were defined as all other reoperations. Competing risk analysis was used to estimate the cumulative incidence of implant removal/revision or amputation. RESULTS: There were 312 reoperations in 113 patients (98 major reoperations in 68 patients and 214 minor reoperations). Seventeen patients (8%) required ≥5 additional operations, and 21 patients (10%) required >1 major reoperation. Although the number of reoperations decreased over time, major and minor reoperations continuously accrued after 10 years. The cumulative incidences of implant removal or revision for any reason at 5, 10, 15, and 20 years were 22.6%, 30.1%, 34.3%, and 42.5%, respectively. Although most implant removals/revisions occurred in the first 10 years, the risk persisted after 10 years, at a mean of 1.24%/year, mainly due to deep infection (1.06%/year). CONCLUSIONS: The long-term outcomes of treatment with a Finn/OSS distal femoral rotating-hinge knee prosthesis showed it to be a durable reconstruction technique. The rate of implant removal/revisions after 10 years was gradual (1.24%/year). Deep infection remains a major late-failure mechanism, and lifetime surveillance for prosthetic problems is needed. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Chromosome 3p loss of heterozygosity and reduced expression of H3K36me3 correlate with longer relapse-free survival in sacral conventional chordoma.

Conventional chordoma is a rare slow-growing malignant tumor of notochordal origin primarily arising at the base of the skull and sacrococcygeal bones. Chordoma may arise from its benign counterpart, benign notochordal cell tumors, and can also undergo dedifferentiation progressing into dedifferentiated chordoma. No study has directly compared the genomic alterations among these tumors comprising a morphologic continuum. Our prior study identified frequent chromosome 3p loss of heterozygosity and minimal deleted regions on chromosome 3 encompassing SETD2, encoding a histone methyltransferase involved in histone H3 lysine 36 trimethylation (H3K36me3). In the present study, we expanded our study to include 65 sacral conventional chordoma cases, 3 benign notochordal cell tumor cases, and 2 dedifferentiated chordoma cases using single nucleotide polymorphism (SNP) array, targeted next-generation sequencing analysis, and immunohistochemistry. We performed immunohistochemical analysis of histone, H3K36me3, and investigated whether there is any association between the clinical behavior and recurrent chromosome or aneuploidy or H3K36me3 protein expression. We found that there is increased genomic instability from benign notochordal cell tumor to conventional chordoma to dedifferentiated chordoma. The highly recurrent genomic aberration, chromosome 3p loss of heterozygosity (occurred in 70% of conventional chordomas), is correlated with longer relapse-free survival, but not with overall survival or metastasis-free survival in sacral chordoma. Chordomas demonstrate variable patterns and levels of H3K36me3 expression, and reduced expression of H3K36me3 showed marginally significant correlation with longer relapse-free survival. Copy number alterations in the genes encoding the H3K36me3 methylation transferase complex and demethylase may account for the altered H3K36me3 expression levels.

What Are the Minimum Clinically Important Differences in SF-36 Scores in Patients with Orthopaedic Oncologic Conditions?

BACKGROUND: The SF-36 is widely used to evaluate the health-related quality of life of patients with musculoskeletal tumors. The minimum clinically important difference (MCID) is useful for interpreting changes in functional scores because it defines the smallest change each patient may perceive. Since the MCID is influenced by the population characteristics, MCIDs of the SF-36 should be defined to reflect the specific conditions of orthopaedic oncology patients. QUESTIONS/PURPOSES: (1) What is the MCID of SF-36 physical component summary (PCS) and mental component summary (MCS) scores in patients with orthopaedic oncologic conditions when calculated with distribution-based methods? (2) What is the MCID of SF-36 PCS and MCS scores in patients with orthopaedic oncologic conditions when calculated by anchor-based methods? METHODS: Of all 960 patients who underwent surgery from 1999 to 2005, 32% (310) of patients who underwent musculoskeletal oncologic surgery and completed two surveys during postoperative follow-up were reviewed. We evaluated a dataset that ended in 2005, completing follow-up of data accrued as part of the cooperative effort between the American Academy of Orthopaedic Surgeons and the Council of Musculoskeletal Specialty Societies to create patient reported quality of life instruments for lower extremity conditions. This effort, started in 1994 was validated and widely accepted by its publication in 2004. We believe the findings from this period are still relevant today because (1) this critical information has never been available for clinicians and researchers to distinguish real differences in outcome among orthopaedic oncology patients, (2) the SF-36 continues to be the best validated and widely used instrument to assess health-related quality of life, and unfortunately (3) there has been no significant change in outcome for oncology patients over the intervening years. SF-36 PCS and MCS are aggregates of the eight scale scores specific to physical and mental dimension (scores range from 0 to 100, with higher scores representing better health). Their responsiveness has been shown postoperatively for several surgical procedures (such as, colorectal surgery). Two different methods were used to calculate the MCID: the distribution-based method, which was based on half the SD of the change in score and standard error of the measurement at baseline, and anchor-based, in which a receiver operating characteristic (ROC) curve analysis was performed. The anchor-based method uses a plain-language question to ask patients how their individual conditions changed when compared with the previous survey. Answer choices were "much better," "somewhat better," "about the same," "somewhat worse," or "much worse." The ROC curve-derived MCIDs were defined as the change in scores from baseline, with sensitivity and specificity to detect differences in patients who stated their outcome was, about the same and those who stated their status was somewhat better or somewhat worse. This approach is based on each patient's perception. It considers that the definition of MCID is the minimal difference each patient can perceive as meaningful. RESULTS: Using the distribution-based method, we found that the MCIDs of the PCS and MCS were 5 and 5 by half the SD, and 6 and 5 by standard error of the measurement. In the anchor-based method, the MCIDs of the PCS and MCS for improvement/deterioration were 4 (area under the curve, 0.82)/-2 (area under the curve, 0.79) and 4 (area under the curve, 0.72)/ (area under the curve, 0.68), respectively. CONCLUSIONS: Since both anchor-based and distribution-based MCID estimates of the SF-36 in patients with musculoskeletal tumors were so similar, we have confidence in the estimates we made, which were about 5 points for both the PCS and the MCS subscales of the SF-36. This suggests that interventions improving SF-36 by less than that amount are unlikely to be perceived by patients as clinically important. Therefore, those interventions may not justify exposing patients to risk, cost, or inconvenience. When applying new interventions to orthopaedic oncology patients going forward, it will be important to consider these MCIDs for evaluation purposes. LEVEL OF EVIDENCE: Level III, diagnostic study.

Rate and risk factors for wound complications after internal hemipelvectomy.

AIMS: Although internal hemipelvectomy is associated with a high incidence of morbidity, especially wound complications, few studies have examined rates of wound complications in these patients or have identified factors associated with the consequences. The present study aimed to: 1) determine the rate of wound and other complications requiring surgery after internal hemipelvectomy; and 2) identify factors that affect the rate of wound complications and can be used to stratify patients by risk of wound complications. METHODS: The medical records of 123 patients undergoing internal hemipelvectomy were retrospectively reviewed, with a focus on both overall complications and wound complications. Logistic regression analyses were performed to examine the association between host, tumour, and surgical factors and rates of postoperative wound complications. RESULTS: The overall rate of postoperative complications requiring surgery was 49.6%. Wound complications were observed in 34.1% of patients, hardware-related complications in 13.2%, graft-related complications in 9.1%, and local recurrence in 5.7%. On multivariate analysis, extrapelvic tumour extension (odds ratio (OR) 23.28; 95% confidence interval (CI), 1.97 to 274.67; p = 0.012), both intra- and extrapelvic tumour extension (OR 46.48; 95% CI, 3.50 to 617.77; p = 0.004), blood transfusion ≥ 20 units (OR 50.28; 95% CI, 1.63 to 1550.32; p = 0.025), vascular sacrifice of the internal iliac artery (OR 64.56; 95% CI, 6.33 to 658.43; p < 0.001), and use of a structural allograft (OR, 6.57; 95% CI, 1.70 to 25.34; p = 0.001) were significantly associated with postoperative wound complications. CONCLUSION: Internal hemipelvectomy is associated with high rates of morbidity, especially wound complications. Several host, tumour, and surgical variables are associated with wound complications. The ability to stratify patients by risk of wound complications can help refine surgical and wound-healing planning and may lead to better outcomes in patients undergoing internal hemipelvectomy. Cite this article: Bone Joint J 2020;102-B(3):280-284.

Genomic Profiling Identifies Association of IDH1/IDH2 Mutation with Longer Relapse-Free and Metastasis-Free Survival in High-Grade Chondrosarcoma.

PURPOSE: Chondrosarcomas are the second most common primary malignant bone tumors. Although histologic grade is the most important factor predicting the clinical outcome of chondrosarcoma, it is subject to interobserver variability. Isocitrate dehydrogenase 1 (IDH1) and IDH2 hotspot mutations were recently found to be frequently mutated in central chondrosarcomas. However, a few published articles have been controversial regarding the association between IDH1/IDH2 mutation status and clinical outcomes in chondrosarcomas. EXPERIMENTAL DESIGN: We performed hotspot sequencing of IDH1 and IDH2 genes in 89 central chondrosarcomas and targeted next-generation sequencing in 54 of them, and then correlated the IDH1/IDH2 mutation status with the patient's clinical outcome. RESULTS: Although no association was discovered between IDH mutation status and the patient's overall survival, IDH1/IDH2 mutation was found to be associated with longer relapse-free and metastasis-free survival in high-grade chondrosarcomas. Genomic profiling reveals TERT gene amplification and ATRX mutation, for the first time, in addition to TERT promoter mutation in a subset (6/30, 20%) of high-grade and dedifferentiated chondrosarcomas. These abnormalities in telomere genes are concurrent with IDH1/IDH2 mutation and with CDKN2A/2B deletion or TP53 mutation, suggesting a possible association and synergy among these genes in chondrosarcoma progression. We found 21% of patients with chondrosarcoma also had histories of second malignancies unrelated to cartilaginous tumors, suggesting possible unknown genetic susceptibility to chondrosarcoma. CONCLUSIONS: IDH1/IDH2 mutations are associated with longer relapse-free and metastasis-free survival in high-grade chondrosarcomas, and they tend to co-occur with TERT mutations and with CDKN2A/2B and TP53 alterations in a subset of high-grade chondrosarcomas.

Association between patient age and the risk of mortality following local recurrence of a sacral chordoma.

BACKGROUND: Local recurrence (LR) of sacral chordoma is a difficult problem and the mortality risk associated with LR remains poorly described. The purpose of this study was to evaluate the risk of mortality in patients with LR and determine if patient age is associated with mortality. METHODS: A total of 218 patients (144 male, 69 female; mean age 59 ± 15 years) with sacrococcygeal chordomas were reviewed. Cumulative incidence functions and competing risks for death due to disease and nondisease mortality were employed to analyze mortality trends following LR. RESULTS: The 10-year overall survival (OS) was 55%. Patients with LR had 44% 10-year OS, similar to patients without (59%; P = .38). The 10-year OS between those less than 55 compared with ≥55 years were similar (69% vs 48%; P = .52). The 10-year death due to disease was worse in patients with LR compared with those without (44% vs 84%; P < .001). In patients without LR, patients ≥55 years were 1.6-fold more likely to experience death due to other causes. CONCLUSIONS: Patients with an LR are more likely to die due to disease. Advanced patient age was associated with higher all-cause mortality following resection of sacral chordoma. LR of chordoma was associated with increased disease-specific mortality, regardless of age.

Treatment of dedifferentiated chordoma: a retrospective study from a large volume cancer center.

OBJECTIVE: Dedifferentiated chordomas (DC) are genetically and clinically distinct from conventional chordomas (CC), exhibiting frequent SMARCB1 alterations and a more aggressive clinical course. We compared treatment and outcomes of DC and CC patients in a retrospective cohort study from a single, large-volume cancer center. METHODS: Overall, 11 DC patients were identified from 1994 to 2017 along with a cohort of 68 historical control patients with CC treated during the same time frame. Clinical variables and outcomes were collected from the medical record and Wilcoxon rank sum or Fisher exact tests were used to make comparisons between the two groups. Kaplan-Meier survival analysis and log-rank tests were used to compare DC and CC overall survival. RESULTS: DC demonstrated a bimodal age distribution at presentation (36% age 0-24; 64% age > 50). DC patients more commonly presented with metastatic disease than CC patients (36% vs. 3% p = 0.000). DC patients had significantly shorter time to local treatment failure after radiation therapy (11.1 months vs. 34.1 months, p = 0.000). The rate of distant metastasis following treatment was significantly higher in DC compared to CC (57% vs. 5%, p = 0.000). The median overall survival after diagnosis for DC was 20 months (95% CI 0-48 months) compared to 155 months (95% CI 94-216 months) for CC (p = 0.007). CONCLUSION: DC patients exhibit significantly higher rates of both synchronous and metachronous metastases, as well as shorter overall survival rates compared to conventional chordoma. The relatively poor survival outcomes with conventional therapies indicate the need to study targeted therapies for the treatment of DC.

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.

Low dose radiotherapy is associated with local complications but not disease control in sacral chordoma.

BACKGROUND: We reviewed the disease control and complications of the treatment of sacrococcygeal chordoma from four tertiary cancer centers with emphasis on the effects of radiotherapy in surgically treated patients. METHODS: A total of 193 patients with primary sacrococcygeal chordoma from 1990 to 2015 were reviewed. There were 124 males, with a mean age of 59 ± 15 years and a mean follow-up of 7 ± 4 years. Eighty-nine patients received radiotherapy with a mean total dose of 61.8 ± 10.9 Gy. RESULTS: The 10-year disease-free and disease-specific survival was 58% and 72%, respectively. Radiation was not associated with local recurrence (hazard ratio [HR], 1.13; 95% confidence interval [CI], 0.59-2.17; P = 0.71), metastases (HR, 0.93; 95% CI, 0.45-1.91; P = 0.85) or disease-specific survival (HR, 0.96; 95% CI, 0.46-2.00; P = 0.91). Higher doses (≥70 Gy; HR, 0.52; 95% CI, 0.20-1.32; P = 0.17) may be associated with reduced local recurrence. Radiotherapy was associated with wound complications (HR, 2.76; 95% CI, 1.64-4.82;, P < 0.001) and sacral stress fractures (HR, 4.73; 95% CI, 1.88-14.38; P < 0.001). CONCLUSIONS: In this multicenter review, radiotherapy was not associated with tumor outcome but associated with complications. The routine use of radiotherapy with en-bloc resection of sacrococcygeal chordomas should be reconsidered in favor of a selective, individualized approach with a radiation dose of ≥70 Gy.

Chemotherapy Curtails Bone Formation From Compliant Compression Fixation of Distal Femoral Endoprostheses.

BACKGROUND: Modulated compliant compressive forces may contribute to durable fixation of implant stems in patients with cancer who undergo endoprosthetic reconstruction after tumor resection. Chemotherapy effects on bone hypertrophy and osteointegration have rarely been studied, and no accepted radiologic method exists to evaluate compression-associated hypertrophy. QUESTIONS/PURPOSES: (1) What was the effect of chemotherapy on the newly formed bone geometry (area) at 1 year and the presumed osteointegration? (2) What clinical factors were associated with the degree of hypertrophy? (3) Did the amount of bone formation correlate with implant fixation durability? (4) Was the amount of new bone generation or chemotherapy administration correlated with Musculoskeletal Tumor Society (MSTS) score? METHODS: Between 1999 and 2013, we performed 245 distal femoral reconstructions for primary or revision oncologic indications. We evaluated 105 patients who received this implant. Ten were excluded because they lacked 2 years of followup and two were lost to followup, leaving 93 patients for review. All underwent distal femur reconstruction with the compliant compressive fixation prosthesis; 49 received postoperative chemotherapy and 44 did not. During this period, the implant was used for oncology patients < 60 years of age without metastases and with > 8 cm of intact, nonirradiated bone distal to the lesser trochanter and ≥ 2.5 mm of cortex. Our cohort included patients with painful loosening of cemented or uncemented stemmed femoral megaprostheses when revision with the compliant compressive device was feasible. Patients with high-grade sarcomas all received chemotherapy, per active Children's Oncology Group protocols, for their tumor diagnosis. At each imaging time point (3, 6, 9, 12, 18, 24 months), we measured the radiographic area of the bone under compression using National Institutes of Health open-access software, any shortening of the spindle-anchor plug segment distance as reflected by the exposed traction bar length, and prosthesis survivorship. Clinical and functional status and MSTS scores were recorded at each followup visit. Duration of prosthesis retention without aseptic loosening or mechanical failure was evaluated using Kaplan-Meier analysis, censoring patients at last followup. RESULTS: Chemotherapy was associated with the amount of overall bone formation in a time-dependent fashion. In the 12 months after surgery there was more bone formation in patients who did not receive postoperative chemotherapy than those who did (60.2 mm, confidence interval [CI] 49.3-71.1 versus 39.1, CI 33.3-44.9; p = 0.001). Chemotherapy was not associated with prosthesis survival. Ten-year implant survival was 85% with chemotherapy and 88% without chemotherapy (p = 0.74). With the number of patients we had, we did not identify any clinical factors that were associated with the amount (area) of hypertrophy. The hypertrophied area was not associated with the durability of implant fixation. MSTS scores were lower in patients treated with chemotherapy (25 versus 28; p = 0.023), but were not correlated with new bone formation. CONCLUSIONS: The relationships among chemotherapy, bone formation, and prosthetic survivorship are complex. Because bone formation is less in the first year when the patient is being treated with chemotherapy, it is not clear if the rehabilitation schedule should be different for those patients receiving chemotherapy compared with those who do not. The relationship between early bone formation and the timing of weightbearing rehabilitation should be evaluated in a multicenter study. LEVEL OF EVIDENCE: Level III, therapeutic study.

Tumor Xenografts of Human Clear Cell Renal Cell Carcinoma But Not Corresponding Cell Lines Recapitulate Clinical Response to Sunitinib: Feasibility of Using Biopsy Samples.

BACKGROUND: Parallel development of preclinical models that recapitulate treatment response observed in patients is central to the advancement of personalized medicine. OBJECTIVE: To evaluate the use of biopsy specimens to develop patient-derived xenografts and the use of corresponding cell lines from renal cell carcinoma (RCC) tumors for the assessment of histopathology, genomics, and treatment response. DESIGN, SETTING, AND PARTICIPANTS: A total of 74 tumor specimens from 66 patients with RCC were implanted into immunocompromised NOD-SCID IL2Rg-/- mice. Four cell lines generated from patients' specimens with clear cell pathology were used for comparative studies. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Preclinical models were established and assessed. Engraftment rates were analyzed using chi-square testing. Analysis of variance (two-way analysis of variance) was conducted to assess tumor growth. RESULTS AND LIMITATIONS: Overall, 33 RCC mouse xenograft models were generated with an overall engraftment rate of 45% (33 of 74). Tumor biopsies engrafted comparably with surgically resected tumors (58% vs 41%; p=0.3). Xenograft tumors and their original tumors showed high fidelity in regard to histology, mutation status, copy number change, and targeted therapy response. Engraftment rates from metastatic tumors were higher but not more significant than primary tumors (54% vs 34%; p=0.091). Our engraftment rate using metastases or biopsies was comparable with recent reports using resected primary tumors. In stark contrast to corresponding cell lines, all tested xenografts recapitulated patients' clinical response to sunitinib. CONCLUSIONS: Patient-derived xenograft models can be effectively established from tumor biopsies. Preclinical xenograft models but not matched cell lines reflected clinical responses to sunitinib. PATIENT SUMMARY: Matched patient-derived clear cell renal cell carcinoma xenografts and cell lines from responsive and refractory patients treated with sunitinib were established and evaluated for pharmacologic response to anti-vascular endothelial growth factor treatment. Both models accurately reflected the genetic characteristics of original tumors, but only xenografts recapitulated drug responses observed in patients. These models could serve as a powerful platform for precision medicine.