Publications by authors named "William C Eward"

71 Publications

Exome sequencing of hepatocellular carcinoma in lemurs identifies potential cancer drivers: A pilot study.

Evol Med Public Health 2022 29;10(1):221-230. Epub 2022 Apr 29.

Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.

Background And Objectives: Hepatocellular carcinoma occurs frequently in prosimians, but the cause of these liver cancers in this group is unknown. Characterizing the genetic changes associated with hepatocellular carcinoma in prosimians may point to possible causes, treatments and methods of prevention, aiding conservation efforts that are particularly crucial to the survival of endangered lemurs. Although genomic studies of cancer in non-human primates have been hampered by a lack of tools, recent studies have demonstrated the efficacy of using human exome capture reagents across primates.

Methodology: In this proof-of-principle study, we applied human exome capture reagents to tumor-normal pairs from five lemurs with hepatocellular carcinoma to characterize the mutational landscape of this disease in lemurs.

Results: Several genes implicated in human hepatocellular carcinoma, including , and , were mutated in multiple lemurs, and analysis of cancer driver genes mutated in these samples identified enrichment of genes involved with degradation and regulation. In addition to these similarities with human hepatocellular carcinoma, we also noted unique features, including six genes that contain mutations in all five lemurs. Interestingly, these genes are infrequently mutated in human hepatocellular carcinoma, suggesting potential differences in the etiology and/or progression of this cancer in lemurs and humans.

Conclusions And Implications: Collectively, this pilot study suggests that human exome capture reagents are a promising tool for genomic studies of cancer in lemurs and other non-human primates.

Lay Summary: Hepatocellular carcinoma occurs frequently in prosimians, but the cause of these liver cancers is unknown. In this proof-of-principle study, we applied human DNA sequencing tools to tumor-normal pairs from five lemurs with hepatocellular carcinoma and compared the lemur mutation profiles to those of human hepatocellular carcinomas.
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http://dx.doi.org/10.1093/emph/eoac016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9086584PMC
April 2022

Investigating readmission rates for patients undergoing oncologic resection and endoprosthetic reconstruction for primary sarcomas and tumors involving bone.

J Surg Oncol 2022 Mar 23. Epub 2022 Mar 23.

Department of Orthopaedic Surgery, Duke University Medical Center, Durham, North Carolina, USA.

Background: Little is known about the drivers of readmission in patients undergoing Orthopaedic oncologic resection. The goal of this study was to identify factors independently associated with 90-day readmission for patients undergoing oncologic resection and subsequent prosthetic reconstruction for primary tumors involving bone.

Methods: This was a retrospective comparative cohort study of patients treated from 2008 to 2019 who underwent endoprosthetic reconstruction for a primary bone tumor or soft tissue tumor involving bone, as well as those who underwent a revision endoprosthetic reconstruction if the primary endoprosthetic reconstruction was performed for an oncologic resection. The primary outcome measure was unplanned 90-day readmission.

Results: A total of 149 patients were identified who underwent 191 surgeries were for a primary bone or soft tissue tumor. The 90-day readmission rate was 28.3%. Female gender, depression, higher tumor grade, vascular reconstruction, longer procedure duration, longer length of stay (LOS), multiple surgeries during an admission and disposition to a Skilled Nursing Facility were associated with readmission (p < 0.05). In a multivariate analysis, female sex, higher tumor grade and longer procedure duration were independently associated with risk of readmission (p < 0.05).

Conclusions: Readmission rates are high following endoprosthetic reconstruction for Orthopaedic oncologic resections. Further work is necessary to help minimize unplanned readmissions.
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http://dx.doi.org/10.1002/jso.26864DOI Listing
March 2022

An integrated comparative physiology and molecular approach pinpoints mediators of breath-hold capacity in dolphins.

Evol Med Public Health 2021 28;9(1):420-430. Epub 2021 Oct 28.

Department of Medicine, Duke University Medical Center, Durham, NC, USA.

Background And Objectives: Ischemic events, such as ischemic heart disease and stroke, are the number one cause of death globally. Ischemia prevents blood, carrying essential nutrients and oxygen, from reaching tissues, leading to cell and tissue death, and eventual organ failure. While humans are relatively intolerant to ischemic events, other species, such as marine mammals, have evolved a unique tolerance to chronic ischemia/reperfusion during apneic diving. To identify possible molecular features of an increased tolerance for apnea, we examined changes in gene expression in breath-holding dolphins.

Methodology: Here, we capitalized on the adaptations possesed by bottlenose dolphins () for diving as a comparative model of ischemic stress and hypoxia tolerance to identify molecular features associated with breath holding. Given that signals in the blood may influence physiological changes during diving, we used RNA-Seq and enzyme assays to examine time-dependent changes in gene expression in the blood of breath-holding dolphins.

Results: We observed time-dependent upregulation of the arachidonate 5-lipoxygenase (ALOX5) gene and increased lipoxygenase activity during breath holding. ALOX5 has been shown to be activated during hypoxia in rodent models, and its metabolites, leukotrienes, induce vasoconstriction.

Conclusions And Implications: The upregulation of ALOX5 mRNA occurred within the calculated aerobic dive limit of the species, suggesting that ALOX5 may play a role in the dolphin's physiological response to diving, particularly in a pro-inflammatory response to ischemia and in promoting vasoconstriction. These observations pinpoint a potential molecular mechanism by which dolphins, and perhaps other marine mammals, respond to the prolonged breath holds associated with diving.
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http://dx.doi.org/10.1093/emph/eoab036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8833867PMC
October 2021

Intraoperative angiography imaging correlates with wound complications following soft tissue sarcoma resection.

J Orthop Res 2022 Jan 10. Epub 2022 Jan 10.

Department of Orthopaedic Surgery, Duke University Medical Center, Durham, North Carolina, USA.

For soft tissue sarcoma patients receiving preoperative radiation therapy, wound complications are common and potentially devastating. The purpose of this study was to assess the feasibility of intraoperative indocyanine green fluorescent angiography (ICGA) as a predictor of wound complications in these patients. A consecutive series of patients with soft tissue sarcoma of the extremities or pelvis who received neoadjuvant radiation and a subsequent radical resection received intraoperative ICGA with the SPY PHI device (Stryker Inc.) at the time of closure. Retrospective analysis of fluorescence signal along multiple points of the wound length was performed and quantified. The primary endpoint was wound complication, defined as delayed wound healing or wound dehiscence, within 3 months of surgery. Fourteen patients with preoperative irradiated soft tissue sarcoma were consecutively imaged. There were six patients with wound complications classified as "aseptic" in five cases. Using the ICGA, blinded surgeons correctly predicted wound complications in 75% of cases. During the inflow phase, a mean ratio of normal of 0.62 maximized the area under the curve (AUC = 0.90) for predicting wound complications with a sensitivity of 100% and specificity of 77.4%. During the peak phase, a mean ratio of normal of 0.55 maximized the AUC (0.95) for predicting wound complications with a sensitivity of 88.9% and a specificity of 100%. Intraoperative use of ICGA may help to predict wound complications in patients undergoing resection of preoperatively irradiated soft tissue sarcomas of the extremities and pelvis.
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http://dx.doi.org/10.1002/jor.25270DOI Listing
January 2022

Extent of tumor fibrosis/hyalinization and infarction following neoadjuvant radiation therapy is associated with improved survival in patients with soft-tissue sarcoma.

Cancer Med 2022 01 27;11(1):194-206. Epub 2021 Nov 27.

Department of Orthopaedics, Duke University, Durham, North Carolina, USA.

Introduction: Current standard of care for most intermediate and high-grade soft-tissue sarcomas (STS) includes limb-preserving surgical resection with either neoadjuvant radiation therapy (NRT) or adjuvant radiation therapy. To date, there have been a few studies that attempt to correlate histopathologic response to NRT with oncologic outcomes in patients with STS.

Methods: Using our institutional database, we identified 58 patients who received NRT followed by surgical resection for primary intermediate or high-grade STS and 34 patients who received surgical resection without NRT but did receive adjuvant radiation therapy or did not receive any radiation therapy. We analyzed four histologic parameters of response to therapy: residual viable tumor, fibrosis/hyalinization, necrosis, and infarction (each ratiometrically determined). Data were stratified into two binary groups. Unadjusted, 5- and 10-year overall survival, and relapsed-free survival (RFS) were calculated using the Kaplan-Meier method.

Results: Analysis of pathologic characteristics showed that patients treated with NRT demonstrate significantly higher tumor infarction, higher tumor fibrosis/hyalinization, and a lower percent viable tumor compared with patients not treated with NRT (p < 0.0001). Based on Kaplan-Meier curve analysis and multivariate cox proportional hazard model for OS and RFS, patients treated with NRT and showing >12.5% tumor fibrosis/hyalinization have significantly higher overall survival and recurrence-free survival at 5 and 10 years.

Discussion And Conclusion: We have identified three histopathologic characteristics-fibrosis, hyalinization, and infarction-that may serve as predictive biomarkers of response to NRT for STS patients. Future prospective studies will be needed to confirm this association.
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http://dx.doi.org/10.1002/cam4.4428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8704179PMC
January 2022

Why Do Patients Undergoing Extremity Prosthetic Reconstruction for Metastatic Disease Get Readmitted?

J Arthroplasty 2022 02 2;37(2):232-237. Epub 2021 Nov 2.

Department of Orthopaedic Surgery, Duke University Medical Center, Durham, NC.

Background: Orthopedic oncology patients are particularly susceptible to increased readmission rates and poor surgical outcomes, yet little is known about readmission rates. The goal of this study is to identify factors independently associated with 90-day readmission for patients undergoing oncologic resection and subsequent prosthetic reconstruction for metastatic disease of the hip and knee.

Methods: This is a retrospective comparative cohort study of all patients treated from 2013 to 2019 at a single tertiary care referral institution who underwent endoprosthetic reconstruction by an orthopedic oncologist for metastatic disease of the extremities. The primary outcome measure was unplanned 90-day readmission.

Results: We identified 112 patients undergoing 127 endoprosthetic reconstruction surgeries. Metastatic disease was most commonly from renal (26.8%), lung (23.6%), and breast (13.4%) cancer. The most common type of skeletal reconstruction performed was simple arthroplasty (54%). There were 43 readmissions overall (33.9%). When controlling for confounding factors, body mass index >40, insurance status, peripheral vascular disease, and longer hospital length of stay were independently associated with risk of readmission (P ≤ .05).

Conclusion: Readmission rates for endoprosthetic reconstructions for metastatic disease are high. Although predicting readmission remains challenging, risk stratification presents a viable option for helping minimize unplanned readmissions.

Level Of Evidence: III.
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http://dx.doi.org/10.1016/j.arth.2021.10.019DOI Listing
February 2022

The Utility of Chest Imaging for Surveillance of Atypical Lipomatous Tumors.

Sarcoma 2021 11;2021:4740924. Epub 2021 Oct 11.

Department of Orthopaedic Surgery, Duke University Medical Center, Durham, NC, USA.

Background: Unlike other soft tissue sarcomas, atypical lipomatous tumors (ALTs) are thought to have a low propensity for metastasis. Despite this, a standard of care for pulmonary metastasis (PM) surveillance has not been established. This study aimed to evaluate the utility of chest imaging for PM surveillance following ALT excision.

Methods: This was a multi-institution, retrospective review of all patients with primary ALTs of the extremities or superficial torso who underwent excision between 2006 and 2018. Minimum follow-up was two years. Long-term survival was evaluated using the Kaplan-Meier method.

Results: 190 patients with ALT were included. Average age was 61.7 years and average follow-up was 58.6 months (24 to 180 months). MDM2 testing was positive in 88 patients (46.3%), and 102 (53.7%) did not receive MDM2 testing. 188 patients (98.9%) had marginal excision, and 127 (66.8%) had marginal or positive margins. Patients received an average of 0.9 CT scans and 1.3 chest radiographs over the surveillance period. 10-year metastasis-free survival was 100%, with no documented deaths from disease.

Conclusions: This study suggests that chest imaging does not have a significant role in PM surveillance following ALT excision, but advanced local imaging and chest surveillance may be considered in cases of local recurrence or concern for dedifferentiation.
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http://dx.doi.org/10.1155/2021/4740924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8523289PMC
October 2021

A Zebrafish Model of Metastatic Colonization Pinpoints Cellular Mechanisms of Circulating Tumor Cell Extravasation.

Front Oncol 2021 23;11:641187. Epub 2021 Sep 23.

Duke Cancer Institute, Duke University Medical Center, Durham, NC, United States.

Metastasis is a multistep process in which cells must detach, migrate/invade local structures, intravasate, circulate, extravasate, and colonize. A full understanding of the complexity of this process has been limited by the lack of ability to study these steps in isolation with detailed molecular analyses. Leveraging a comparative oncology approach, we injected canine osteosarcoma cells into the circulation of transgenic zebrafish with fluorescent blood vessels in a biologically dynamic metastasis extravasation model. Circulating tumor cell clusters that successfully extravasated the vasculature as multicellular units were isolated under imaging (n = 6). These extravasation-positive tumor cell clusters sublines were then molecularly profiled by RNA-Seq. Using a systems-level analysis, we pinpointed the downregulation of KRAS signaling, immune pathways, and extracellular matrix (ECM) organization as enriched in extravasated cells (p < 0.05). Within the extracellular matrix remodeling pathway, we identified versican () as consistently upregulated and central to the ECM gene regulatory network (p < 0.05). Versican expression is prognostic for a poorer metastasis-free and overall survival in patients with osteosarcoma. Together, our results provide a novel experimental framework to study discrete steps in the metastatic process. Using this system, we identify the versican/ECM network dysregulation as a potential contributor to osteosarcoma circulating tumor cell metastasis.
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http://dx.doi.org/10.3389/fonc.2021.641187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8495265PMC
September 2021

Identifying Modifiable and Non-modifiable Risk Factors of Readmission and Short-Term Mortality in Chondrosarcoma: A National Cancer Database Study.

Ann Surg Oncol 2022 Feb 27;29(2):1392-1408. Epub 2021 Sep 27.

Department of Orthopaedic Surgery, Duke University Hospital, Durham, NC, USA.

Background: Limited data are available to inform the risk of readmission and short-term mortality in musculoskeletal oncology. The goal of this study was to identify factors independently associated with 30-day readmission and 90-day mortality following surgical resection of chondrosarcoma.

Methods: We retrospectively reviewed 6653 patients following surgical resection of primary chondrosarcoma in the National Cancer Database (2004-2017). Both demographic and clinicopathologic variables were assessed for correlation with readmission and short-term mortality utilizing univariate and multivariate logistic regression modeling.

Results: Of 220 readmissions (3.26%), risk factors independently associated with an increased risk of unplanned 30-day readmission included Charlson-Deyo Comorbidity Index (CDCC) (odds ratio [OR] 1.31; p = 0.027), increasing American Joint Committee on Cancer (AJCC) stage (OR 1.31; p = 0.004), undergoing major amputation (OR 2.38; p = 0.001), and axial skeletal location (OR 1.51; p = 0.028). A total of 137 patients died within 90 days of surgery (2.25%). Risk factors associated with increased mortality included the CDCC (OR 1.60; p = 0.001), increasing age (OR 1.06; p < 0.001), having Medicaid insurance status (OR 3.453; p = 0.005), living in a zip code with a higher educational attainment (OR 1.59; p = 0.003), increasing AJCC stage (OR 2.32; p < 0.001), longer postoperative length of stay (OR 1.015; p = 0.033), and positive surgical margins (OR 2.75; p = 0.001). Although a majority of the cohort did not receive radiation therapy (88.8%), receiving radiotherapy (OR 0.132; p = 0.010) was associated with a decreased risk of short-term mortality.

Conclusions: Several tumor, treatment, and patient factors can help inform the risk of readmission and short-term mortality in patients with surgically treated chondrosarcoma.
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http://dx.doi.org/10.1245/s10434-021-10802-8DOI Listing
February 2022

Reverse total shoulder arthroplasty for oncologic reconstruction of the proximal humerus: a systematic review.

J Shoulder Elbow Surg 2021 Nov 15;30(11):e647-e658. Epub 2021 Jul 15.

Department of Orthopaedic Surgery, Duke University Medical Center, Durham, NC, USA.

Background: In recent years, there has been growing interest in the use of reverse total shoulder arthroplasty (rTSA) for reconstruction of the proximal humerus after oncologic resection. However, the indications and outcomes of oncologic rTSA remain unclear.

Methods: We conducted a systematic review to identify studies that reported outcomes of patients who underwent rTSA for oncologic reconstruction of the proximal humerus. Extracted data included demographic characteristics, indications, operative techniques, outcomes, and complications. Weighted means were calculated according to sample size.

Results: Twelve studies were included, containing 194 patients who underwent rTSA for oncologic reconstruction of the proximal humerus. The mean patient age was 48 years, and 52% of patients were male. Primary malignancies were present in 55% of patients; metastatic disease, 30%; and benign tumors, 9%. The mean humeral resection length was 12 cm. The mean postoperative Musculoskeletal Tumor Society score was 78%; Constant score, 60; and Toronto Extremity Salvage Score, 77%. The mean complication rate was 28%, with shoulder instability accounting for 63% of complications. Revisions were performed in 16% of patients, and the mean implant survival rate was 89% at a mean follow-up across studies of 53 months.

Conclusions: Although the existing literature is of poor study quality, with a high level of heterogeneity and risk of bias, rTSA appears to be a suitable option in appropriately selected patients undergoing oncologic resection and reconstruction of the proximal humerus. The most common complication is instability. Higher-quality evidence is needed to help guide decision making on appropriate implant utilization for patients undergoing oncologic resection of the proximal humerus.
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http://dx.doi.org/10.1016/j.jse.2021.06.004DOI Listing
November 2021

Identifying Modifiable and Non-modifiable Risk Factors of Readmission and Short-Term Mortality in Osteosarcoma: A National Cancer Database Study.

Ann Surg Oncol 2021 Nov 20;28(12):7961-7972. Epub 2021 May 20.

Department of Orthopaedic Surgery, Duke University Hospital, Durham, NC, USA.

Background: There are limited data to inform risk of readmission and short-term mortality in musculoskeletal oncology. The goal of this study was to identify factors independently associated with 30-day readmission and 90-day mortality following surgical resection of osteosarcoma.

Methods: We retrospectively reviewed patients (n = 5293) following surgical resection of primary osteosarcoma in the National Cancer Database (2004-2015). Univariate and multivariate methods were used to correlate variables with readmission and short-term mortality.

Results: Of 210 readmissions (3.97%), risk factors independently associated with unplanned 30-day readmission included comorbidity burden (odds ratio [OR] 2.4, p = 0.042), Medicare insurance (OR 1.9, p = 0.021), and axial skeleton location (OR 1.5, p = 0.029). A total of 91 patients died within 90 days of their surgery (1.84%). Risk factors independently associated with mortality included age (hazard ratio 1.1, p < 0.001), increasing comorbidity burden (OR 6.6, p = 0.001), higher grade (OR 1.7, p = 0.007), increasing tumor size (OR 2.2, p = 0.03), metastatic disease at presentation (OR 8.5, p < 0.001), and amputation (OR 2.0, p = 0.04). Chemotherapy was associated with a decreased risk of short-term mortality (p < 0.001).

Conclusions: Several trends were clear: insurance status, tumor location and comorbidity burden were independently associated with readmission rates, while age, amputation, grade, tumor size, metastatic disease, and comorbidity burden were independently associated with short-term mortality.
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http://dx.doi.org/10.1245/s10434-021-10099-7DOI Listing
November 2021

Treatment of Chondroblastoma with Denosumab: A Case Report with a Correlative Analysis of Effect on the RANK Signaling Pathway.

JBJS Case Connect 2021 05 17;11(2). Epub 2021 May 17.

Department of Orthopaedic Surgery, Duke University Medical Center, Durham, North Carolina.

Case: A 15-year-old boy with chondroblastoma of the right hemipelvis presented with significant periacetabular bone destruction. Neoadjuvant denosumab treatment facilitated initial joint preserving surgery. Unfortunately, he experienced 2 local recurrences and underwent wide surgical resection 2 years after his initial diagnosis.

Conclusion: Inhibition of the receptor activator of NF-κB (RANK)/RANK ligand (RANK-L) pathway with denosumab has been used neoadjuvantly for the treatment of giant cell tumor of bone, but its role in the treatment of chondroblastoma is less understood. This patient's clinical response and effect on cellular RANK/RANK-L activity support the consideration of denosumab in the treatment algorithm for other osteolytic bone tumors such as chondroblastoma.
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http://dx.doi.org/10.2106/JBJS.CC.20.00178DOI Listing
May 2021

Humeral Shaft Fracture With Placement of an Intramedullary Nail Through an Unrecognized Sarcoma.

J Am Acad Orthop Surg Glob Res Rev 2021 02 19;5(2). Epub 2021 Feb 19.

From the Duke University School of Medicine, Durham, NC (Mr. Cullen, Mr. Flamant, and Mr. Ferlauto); The University of Houston Health Science Center, Houston, TX (Dr. Okwumabua); the Department of Orthopaedic Surgery, Duke University Medical Center, Durham, NC (Dr. Brigman and Dr. Eward); and Duke Cancer Institute, Durham, NC (Dr. Brigman and Dr. Eward).

Case: A 72-year-old man underwent intramedullary nailing of a humeral diaphysis fracture with passage through an unrecognized pathologic fracture. Four months later, a biopsy of a soft-tissue mass in the arm revealed pleomorphic undifferentiated sarcoma. Only after local recurrence and forequarter amputation was the story of a pathologic fracture through undifferentiated pleomorphic sarcomas of bone clear. The patient developed metastatic disease and died after 2 years postoperatively.

Discussion: Orthopaedic surgeons should consider sarcoma when assessing patients with fractures of unknown etiology and an inappropriate mechanism because the placement of an intramedullary device through a sarcoma of bone has consequences.
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http://dx.doi.org/10.5435/JAAOSGlobal-D-20-00142DOI Listing
February 2021

A Comparative Oncology Drug Discovery Pipeline to Identify and Validate New Treatments for Osteosarcoma.

Cancers (Basel) 2020 Nov 11;12(11). Epub 2020 Nov 11.

Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.

Background: Osteosarcoma is a rare but aggressive bone cancer that occurs primarily in children. Like other rare cancers, treatment advances for osteosarcoma have stagnated, with little improvement in survival for the past several decades. Developing new treatments has been hampered by extensive genomic heterogeneity and limited access to patient samples to study the biology of this complex disease.

Methods: To overcome these barriers, we combined the power of comparative oncology with patient-derived models of cancer and high-throughput chemical screens in a cross-species drug discovery pipeline.

Results: Coupling in vitro high-throughput drug screens on low-passage and established cell lines with in vivo validation in patient-derived xenografts we identify the proteasome and CRM1 nuclear export pathways as therapeutic sensitivities in osteosarcoma, with dual inhibition of these pathways inducing synergistic cytotoxicity.

Conclusions: These collective efforts provide an experimental framework and set of new tools for osteosarcoma and other rare cancers to identify and study new therapeutic vulnerabilities.
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http://dx.doi.org/10.3390/cancers12113335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696249PMC
November 2020

Limb salvage versus amputation in patients with osteosarcoma of the extremities: an update in the modern era using the National Cancer Database.

BMC Cancer 2020 Oct 14;20(1):995. Epub 2020 Oct 14.

Department of Orthopaedic Surgery, Duke University Hospital, 311 Trent Drive, Durham, NC, 27710, USA.

Background: Historically, amputation was the primary surgical treatment for osteosarcoma of the extremities; however, with advancements in surgical techniques and chemotherapies limb salvage has replaced amputation as the dominant treatment paradigm. This study assessed the type of surgical resection chosen for osteosarcoma patients in the twenty-first century.

Methods: Utilizing the largest registry of primary osteosarcoma, the National Cancer Database (NCDB), we retrospectively analyzed patients with high grade osteosarcoma of the extremities from 2004 through 2015. Differences between patients undergoing amputation and patients undergoing limb salvage are described. Unadjusted five-year overall survival between patients who received limb salvage and amputation was assessed utilizing Kaplan Meier curves. A multivariate Cox proportional hazard model and propensity matched analysis was used to determine the variables independently correlated with survival.

Results: From a total of 2442 patients, 1855 underwent limb salvage and 587 underwent amputation. Patients undergoing amputation were more likely to be older, male, uninsured, and live in zip codes associated with lower income. Patients undergoing amputation were also more likely to have larger tumors, more comorbid conditions, and metastatic disease at presentation. After controlling for confounders, limb salvage was associated with a significant survival benefit over amputation (HR: 0.70; p < 0.001). Although this may well reflect underlying biases impacting choice of treatment, this survival benefit remained significant after propensity matched analysis of all significantly different independent variables (HR: 0.71; p < 0.01).

Conclusion: Among patients in the NCDB, amputation for osteosarcoma is associated with advanced age, advanced stage, larger tumors, greater comorbidities, and lower income. Limb salvage is associated with a significant survival benefit, even when controlling for significant confounding variables and differences between cohorts.
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http://dx.doi.org/10.1186/s12885-020-07502-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557006PMC
October 2020

Tumor Subtype Determines Therapeutic Response to Chimeric Polypeptide Nanoparticle-based Chemotherapy in -deleted Mouse Models of Sarcoma.

Clin Cancer Res 2020 09 27;26(18):5036-5047. Epub 2020 Jul 27.

Department of Radiation Oncology, Duke University School of Medicine, Durham, North Carolina.

Purpose: Nanoparticle-encapsulated drug formulations can improve responses to conventional chemotherapy by increasing drug retention within the tumor and by promoting a more effective antitumor immune response than free drug. New drug delivery modalities are needed in sarcomas because they are often chemoresistant cancers, but the rarity of sarcomas and the complexity of diverse subtypes makes it challenging to investigate novel drug formulations.

Experimental Design: New drug formulations can be tested in animal models of sarcomas where the therapeutic response of different formulations can be compared using mice with identical tumor-initiating mutations. Here, using Cre/loxP and CRISPR/Cas9 techniques, we generated two distinct mouse models of -deleted soft-tissue sarcoma: malignant peripheral nerve sheath tumor (MPNST) and undifferentiated pleomorphic sarcoma (UPS). We used these models to test the efficacy of chimeric polypeptide doxorubicin (CP-Dox), a nanoscale micelle formulation, in comparison with free doxorubicin.

Results: The CP-Dox formulation was superior to free doxorubicin in MPNST models. However, in UPS tumors, CP-Dox did not improve survival in comparison with free doxorubicin. While CP-Dox treatment resulted in elevated intratumoral doxorubicin concentrations in MPNSTs, this increase was absent in UPS tumors. In addition, elevation of CD8 T cells was observed exclusively in CP-Dox-treated MPNSTs, although these cells were not required for full efficacy of the CP nanoparticle-based chemotherapy.

Conclusions: These results have important implications for treating sarcomas with nanoparticle-encapsulated chemotherapy by highlighting the tumor subtype-dependent nature of therapeutic response.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641033PMC
September 2020

Defining a textbook surgical outcome for patients undergoing surgical resection of intermediate and high-grade soft tissue sarcomas of the extremities.

J Surg Oncol 2020 Oct 21;122(5):884-896. Epub 2020 Jul 21.

Department of Orthopaedic Surgery, Duke University, Durham, North Carolina.

Background: Quality measures for the surgical management soft tissue sarcoma of the extremity are limited. The purpose of this study was to define a textbook surgical outcome (TO) for soft tissue sarcoma of the extremities (STS-E) and to examine its associations with hospital volume and overall survival.

Methods: All patients in the National Cancer Database undergoing resection of primary STS-E between 2004 and 2015 were identified. The primary outcome was a TO, defined as: hospital length of stay (LOS) <75th percentile, survival >90 days from the date of surgery, no readmission within 30 days of discharge, and negative surgical margins (R0 resection).

Results: Overall, 7658 patients met criteria for inclusion; a TO was achieved in 4291 (56%) patients. Of patients who did not achieve TOs, 51.9% (n = 1748) had an extended LOS, and 47.3% (n = 1591) did not have negative margins. Older age, more medical comorbidities, and non-white or black race were independently associated with not receiving a TO (P = .034). With respect to tumor and treatment characteristics, larger tumor size, lower extremity location and higher grade were independently associated with not receiving a TO (P < .001). Hospital volume was not associated with a TO. TOs conferred a significant survival benefit (hazrds ratio = 0.71 [0.65-0.78], P < .001). A TO was associated with a 27.5% longer survival time (P < .001).

Conclusions: This study defined a TO in intermediate and high-grade STS-E and demonstrated that this outcome measure is associated with overall survival. Facility volume was not associated with a TO.
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http://dx.doi.org/10.1002/jso.26087DOI Listing
October 2020

Extirpative Cultures Reveal Infectious Pubic Bone Osteomyelitis in Prostate Cancer Survivors With Urinary-Pubic Symphysis Fistulae (UPF).

Urology 2020 08 8;142:221-225. Epub 2020 May 8.

Genitourinary Cancer Survivorship Program, Division of Urology, Duke University Medical Center, Durham, NC.

Objective: To examine the infectious features of patients with urinary pubic symphysis fistula (UPF) and their association with osteomyelitis.

Methods: We conducted a review of our quality improvement database for 36 patients with UPF undergoing bone resection and extirpative surgery from October 2012 to January 2019. An assessment of bone and urine cultures was carried out along with surgical, radiologic, and demographic data. We analyzed descriptive statistics and used Fisher Exact Tests and unpaired Welch t tests to assess for associations with positive bone cultures.

Results: In our cohort, 33 patients (91.7%) had positive bone cultures with the 3 most common organisms being candida (22.0%), enterococcus (18.0%), and pseudomonas (10.0%). There was a correlation between positive preoperative urine culture and positive bone culture (P <.01), with 63.0% of those with positive urine cultures growing the same organism on bone culture.

Conclusion: In this series, 91.7% of patients undergoing extirpative surgery for UPF at our institution have positive bone cultures at time of pubic bone debridement. Additionally, we demonstrate a statistically significant correlation between positive urine cultures and positive bone cultures in these patients. This supports the need for a multidisciplinary approach including infectious disease, orthopedic surgery and reconstructive urology in order to address this complex clinical condition.
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http://dx.doi.org/10.1016/j.urology.2020.04.095DOI Listing
August 2020

Preclinical Testing of a Novel Niclosamide Stearate Prodrug Therapeutic (NSPT) Shows Efficacy Against Osteosarcoma.

Mol Cancer Ther 2020 07 5;19(7):1448-1461. Epub 2020 May 5.

Department of Orthopaedic Surgery, Duke University Medical Center, Durham, North Carolina.

Therapeutic advances for osteosarcoma have stagnated over the past several decades, leading to an unmet clinical need for patients. The purpose of this study was to develop a novel therapy for osteosarcoma by reformulating and validating niclosamide, an established anthelminthic agent, as a niclosamide stearate prodrug therapeutic (NSPT). We sought to improve the low and inefficient clinical bioavailability of oral dosing, especially for the relatively hydrophobic classes of anticancer drugs. Nanoparticles were fabricated by rapid solvent shifting and verified using dynamic light scattering and UV-vis spectrophotometry. NSPT efficacy was then studied for cell viability, cell proliferation, and intracellular signaling by Western blot analysis; pulmonary metastatic assay model; and pharmacokinetic and lung mouse metastatic model of osteosarcoma. NSPT formulation stabilizes niclosamide stearate against hydrolysis and delays enzymolysis; increases circulation with approximately 5 hours; reduces cell viability and cell proliferation in human and canine osteosarcoma cells at 0.2-2 μmol/L IC; inhibits recognized growth pathways and induces apoptosis at 20 μmol/L; eliminates metastatic lesions in the lung metastatic model; and when injected intravenously at 50 mg/kg weekly, it prevents metastatic spread in the lungs in a mouse model of osteosarcoma over 30 days. In conclusion, niclosamide was optimized for preclinical drug delivery as a unique prodrug nanoparticle injected intravenously at 50 mg/kg (1.9 mmol/L). This increased bioavailability of niclosamide in the blood stream prevented metastatic disease in the mouse. This chemotherapeutic strategy is now ready for canine trials, and if successful, will be targeted for human trials in patients with osteosarcoma.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-0689DOI Listing
July 2020

Does facility volume influence survival in patients with primary malignant bone tumors of the vertebral column? A comparative cohort study.

Spine J 2020 07 4;20(7):1106-1113. Epub 2020 Mar 4.

Department of Orthopaedic Surgery, Duke University Medical Center, Durham, NC, USA.

Background Context: Facility volume has been correlated with survival in many cancers. This relationship has not been established in primary malignant bone tumors of the vertebral column (BTVC).

Purpose: To investigate whether facility patient volume is associated with overall survival in patients with primary malignant BTVCs.

Study Design: Retrospective comparative cohort.

Patient Sample: Adult patients with chordomas, chondrosarcomas, or osteosarcomas of the mobile spine.

Outcome Measures: Five-year survival.

Methods: We retrospectively analyzed 733 patients with primary malignant BTVCs in the national cancer database from 2004 through 2015. Univariate and multivariate analyses were used to correlate specific outcome measures with facility volume. Volume was stratified based on cumulative martingale residuals to determine the inflection point of negative to positive impact on survival based on the patient cohort. Long-term survival was compared between patients treated at high and low volume using the Kaplan-Meier method. Only patients with malignant primary tumors were considered eligible for inclusion; patients with incomplete treatment data or benign tumors were excluded.

Results: Patients treated at high-volume centers (HVCs) were younger (p=.0003) and more likely to be insured (p<.0001). There were no significant differences in tumor characteristics. Patients treated at high-volume facilities had improved 5-year survival of 71% versus 58% at low-volume centers (p<.0001). Patients treated at HVCs were more likely to receive surgical treatment (91% vs. 80%, p<.0001); if surgery was performed, they were more likely to undergo an en bloc resection (48% vs. 30%, p<.0001). However, there were no differences in margin status or utilization of radiotherapy or chemotherapy between HVCs and low-volume centers. In a multivariate analysis, facility volume was independently associated with improved survival overall (HR 0.75 [0.58-0.97], p=.03).

Conclusions: Primary malignant BTVCs are rare, even for HVCs. Despite this, patient survival was significantly improved when treatment was performed at HVCs.
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http://dx.doi.org/10.1016/j.spinee.2020.02.020DOI Listing
July 2020

From the Clinic to the Bench and Back Again in One Dog Year: How a Cross-Species Pipeline to Identify New Treatments for Sarcoma Illuminates the Path Forward in Precision Medicine.

Front Oncol 2020 11;10:117. Epub 2020 Feb 11.

Department of Orthopaedic Surgery, Duke University Medical Center, Durham, NC, United States.

Cancer drug discovery is an inefficient process, with more than 90% of newly-discovered therapies failing to gain regulatory approval. Patient-derived models of cancer offer a promising new approach to identify new treatments; however, for rare cancers, such as sarcomas, access to patient samples is limited, which precludes development of patient-derived models. To address the limited access to patient samples, we have turned to pet dogs with naturally-occurring sarcomas. Although sarcomas make up <1% of all human cancers, sarcomas represent 15% of cancers in dogs. Because dogs have similar immune systems, an accelerated pace of cancer progression, and a shared environment with humans, studying pet dogs with cancer is ideal for bridging gaps between mouse models and human cancers. Here, we present our cross-species personalized medicine pipeline to identify new therapies for sarcomas. We explore this process through the focused study of a pet dog, Teddy, who presented with six synchronous leiomyosarcomas. Using our pipeline we identified proteasome inhibitors as a potential therapy for Teddy. Teddy was treated with bortezomib and showed a varied response across tumors. Whole exome sequencing revealed substantial genetic heterogeneity across Teddy's recurrent tumors and metastases, suggesting that intra-patient heterogeneity and tumoral adaptation were responsible for the heterogeneous clinical response. Ubiquitin proteomics coupled with exome sequencing revealed multiple candidate driver mutations in proteins related to the proteasome pathway. Together, our results demonstrate how the comparative study of canine sarcomas offers important insights into the development of personalized medicine approaches that can lead to new treatments for sarcomas in both humans and canines.
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http://dx.doi.org/10.3389/fonc.2020.00117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026496PMC
February 2020

The Role of Radiotherapy for Chordoma Patients Managed With Surgery: Analysis of the National Cancer Database.

Spine (Phila Pa 1976) 2020 Jun;45(12):E742-E751

Department of Orthopaedic Surgery, Duke University Medical Center, Durham, NC.

Study Design: Retrospective review.

Objective: To determine if adjuvant radiation therapy (RT) improves overall survival (OS) following surgical resection of chordomas.

Summary Of Background Data: The role of RT for the treatment of chordomas remains incompletely described. Previous studies have not found adjuvant RT to improve OS, but these studies did not group patients based on surgical margin status or radiation dose or modality. We used the National Cancer Database to investigate the role of RT in chordomas following surgical resection.

Methods: Patients were stratified based on surgical margin status (positive vs. negative). Utilizing the Kaplan-Meier method, OS was compared between treatment modalities (surgical resection alone, therapeutic RT alone, and surgical resection plus therapeutic RT). OS was subsequently compared between patients treated with palliative dose (<40 Gy), low dose (40-65 Gy), and high dose (>65 Gy) RT. Similarly, OS was compared between advanced RT modalities including proton beam therapy (PBT) and intensity-modulated radiation therapy (IMRT), stereotactic radiosurgery (SRS), and external beam radiation therapy (EBRT). A multivariable model was used to determine adjusted variables predictive of mortality.

Results: One thousand four hundred seventy eight chordoma patients were identified; skull base (n = 567), sacral (n = 551), and mobile spine (n = 360). Surgical resection and therapeutic adjuvant RT improved 5-year survival in patients with positive surgical margins (82% vs. 71%, P = 0.03). No clear survival benefit was observed with the addition of adjuvant RT in patients with negative surgical margins. High dose RT was associated with improved OS compared with palliative and low dose RT (P < 0.001). Advanced RT techniques and SRS were associated with improved OS compared with EBRT. In the multivariate analysis high dose advanced RT (>65 Gy) was superior to EBRT.

Conclusion: Patients with positive surgical margins benefit from adjuvant RT. Optimal OS is associated with adjuvant RT administered with advanced techniques and cumulative dose more than 65 Gy.

Level Of Evidence: 4.
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http://dx.doi.org/10.1097/BRS.0000000000003406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649561PMC
June 2020

Recurrent Extradural Myxopapillary Ependymoma With Oligometastatic Spread.

Front Oncol 2019 28;9:1322. Epub 2019 Nov 28.

The Preston Robert Tisch Brain Tumor Center, Duke University Health System, Durham, NC, United States.

Myxopapillary ependymomas are a slow-growing, grade I type glial tumor in the lumbosacral region. More rarely, they can present as extradural, subcutaneous sacrococcygeal, or perisacral masses, and it is under these circumstances that they are more likely to spread. Here, we report the presentation of a sacrococcygeal mass in patient that was initially resected confirming extradural myxopapillary ependymoma. At initial resection, multiple small pulmonary nodules were detected. This mass recurred 2 years later at the resection site with an interval increase in the previously imaged pulmonary nodules. Resection of both the post-sacral mass and largest lung metastasis confirmed recurrent myxopapillary ependymoma with oligometastatic spread. Because these tumors are rare, with extradural presentation being even more infrequent, to this date there are no definitive therapeutic guidelines for initial treatment and continued surveillance. For myxopapillary ependymoma, current standard of care is first-line maximal surgical resection with or without postoperative radiotherapy depending on the extent of disease and extent of resection. However, there remains insufficient evidence on the role of radiotherapy to oligometastatic foci in providing any further survival benefit or extending time to recurrence. Thus, prospective studies assessing the role of upfront treatment of oligometastases with local resection and adjuvant radiotherapy are needed for improved understanding of extradural myxopapillary ependymoma.
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http://dx.doi.org/10.3389/fonc.2019.01322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892774PMC
November 2019

Revisiting the Role of Radiation Therapy in Chondrosarcoma: A National Cancer Database Study.

Sarcoma 2019 13;2019:4878512. Epub 2019 Oct 13.

Department of Orthopaedic Surgery, Duke University Medical Center, 2301 Erwin Rd, Durham, NC 27710, USA.

Background: Although chondrosarcomas (CS) are mostly considered radioresistant, advancements in radiotherapy have brought attention to its use in these patients. Using the largest registry of primary bone tumors, the National Cancer Database (NCDB), we sought to better characterize the current use of radiotherapy in CS patients and identify any potential survival benefit with higher radiation doses and advanced radiation therapies.

Methods: We retrospectively analyzed CS patients in the NCDB from 2004 to 2015 who underwent radiotherapy. The Kaplan-Meier method with statistical comparisons was used to identify which individual variables related to dosage and delivery modality were associated with improved 5-year survival rates. Multivariate proportional hazards analyses were performed to determine independent predictors of survival.

Results: Of 5,427 patients with a histologic diagnosis of chondrosarcoma, 680 received a form of radiation therapy (13%). The multivariate proportional hazards analysis controlling for various patient, tumor, and treatment variables, including RT dose and modality, demonstrated that while overall radiation therapy (RT) was not associated with improved survival (HR 0.96, 95% CI 0.76-1.20), when examining just the patient cohort with positive surgical margins, RT trended towards improved survival (HR 0.81, 95% CI 0.58-1.13). When comparing advanced and conventional RT modalities, advanced RT was associated with significantly decreased mortality (HR 0.55, 95% CI 0.38-0.80). However, advanced modality and high-dose RT both trended only toward improved survival compared to patients who did not receive any RT (HR 0.74, 95% CI 0.52-1.06 and HR 0.93, 95% CI 0.71-1.21, respectively).

Conclusions: Despite the suggested radioresistance of CS, modern radiotherapies may present a treatment option for certain patients. Our results support a role for high-dose, advanced radiation therapies in selected high-risk CS patients with tumors in surgically challenging locations or unplanned positive margins. While there is an associated survival rate benefit, further, prospective studies are needed for validation.
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http://dx.doi.org/10.1155/2019/4878512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815626PMC
October 2019

Improving Cancer Drug Discovery by Studying Cancer across the Tree of Life.

Mol Biol Evol 2020 Jan;37(1):11-17

Duke Cancer Institute, Durham, NC.

Despite a considerable expenditure of time and resources and significant advances in experimental models of disease, cancer research continues to suffer from extremely low success rates in translating preclinical discoveries into clinical practice. The continued failure of cancer drug development, particularly late in the course of human testing, not only impacts patient outcomes, but also drives up the cost for those therapies that do succeed. It is clear that a paradigm shift is necessary if improvements in this process are to occur. One promising direction for increasing translational success is comparative oncology-the study of cancer across species, often involving veterinary patients that develop naturally-occurring cancers. Comparative oncology leverages the power of cross-species analyses to understand the fundamental drivers of cancer protective mechanisms, as well as factors contributing to cancer initiation and progression. Clinical trials in veterinary patients with cancer provide an opportunity to evaluate novel therapeutics in a setting that recapitulates many of the key features of human cancers, including genomic aberrations that underly tumor development, response and resistance to treatment, and the presence of comorbidities that can affect outcomes. With a concerted effort from basic scientists, human physicians and veterinarians, comparative oncology has the potential to enhance the cost-effectiveness and efficiency of pipelines for cancer drug discovery and other cancer treatments.
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http://dx.doi.org/10.1093/molbev/msz254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204703PMC
January 2020

Common genetic variation and risk of osteosarcoma in a multi-ethnic pediatric and adolescent population.

Bone 2020 01 13;130:115070. Epub 2019 Sep 13.

Department of Epidemiology and Biostatistics, University of California, San Francisco, United States; Duke Cancer Institute, Duke University, United States; Department of Neurosurgery, Duke University, United States. Electronic address:

Osteosarcoma, a malignant primary bone tumor most commonly diagnosed in children and adolescents, has a poorly understood genetic etiology. Genome-wide association studies (GWAS) and candidate-gene analyses have identified putative risk variants in subjects of European ancestry. However, despite higher incidence among African-American and Hispanic children, little is known regarding common heritable variation that contributes to osteosarcoma incidence and clinical presentation across racial/ethnic groups. In a multi-ethnic sample of non-Hispanic white, Hispanic, African-American and Asian/Pacific Islander children (537 cases, 2165 controls), we performed association analyses assessing previously-reported loci for osteosarcoma risk and metastasis, including meta-analysis across racial/ethnic groups. We also assessed a previously described association between genetic predisposition to longer leukocyte telomere length (LTL) and osteosarcoma risk in this independent multi-ethnic dataset. In our sample, we were unable to replicate previously-reported loci for osteosarcoma risk or metastasis detected in GWAS of European-ancestry individuals in either ethnicity-stratified analyses or meta-analysis across ethnic groups. Our analyses did confirm that genetic predisposition to longer LTL is a risk factor for osteosarcoma (OR: 1.22; 95% CI: 1.09-1.36; P = 3.8 × 10), and the strongest effect was seen in Hispanic subjects (OR: 1.32; 95% CI: 1.12-1.54, P = 6.2 × 10). Our findings shed light on the replicability of osteosarcoma risk loci across ethnicities and motivate further characterization of these genetic factors in diverse clinical cohorts.
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http://dx.doi.org/10.1016/j.bone.2019.115070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885126PMC
January 2020

Immune dysregulation and osteosarcoma: Staphylococcus aureus downregulates TGF-β and heightens the inflammatory signature in human and canine macrophages suppressed by osteosarcoma.

Vet Comp Oncol 2020 Mar 15;18(1):64-75. Epub 2019 Oct 15.

Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina.

Since William Coley utilized bacterial immunotherapy to treat sarcomas in the late 19th century, an association between infection and improved survival has been reported for human and canine osteosarcoma patients. One of the reasons for this improved survival is likely a reactivation of the host immune system towards an inflammatory anti-tumour response, and one of the key players is the macrophage. Yet, despite their importance, the response of macrophages to infectious agents in the context of osteosarcoma has not been thoroughly evaluated. The aim of this study was to evaluate how in vitro exposure to a bacterial agent (Staphylococcus aureus) influenced canine and human macrophage differentiation in the presence of osteosarcoma. Our hypothesis was that S. aureus would, in the presence of osteosarcoma, induce a macrophage phenotype with significantly increased inflammatory signatures. Consistent with our hypothesis, human macrophages co-cultured with osteosarcoma and S. aureus exhibited increased IFN-γ, TNF-α and IL-12p70 cytokine secretion, decreased TGF-β cytokine secretion and increased mRNA expression of TNF-α when compared with macrophages co-cultured with osteosarcoma and to macrophages cultured alone. Canine macrophages similarly exhibited increased IFN-γ and TNF-α cytokine secretion, decreased TGF-β cytokine secretion, increased mRNA expression of TNF-α and increased surface receptor expression of CD80 when co-cultured with osteosarcoma and S. aureus. Collectively, the findings of this study suggest that infection upregulates the inflammatory immune response to counteract osteosarcoma-induced immune suppression. This work informs a potential therapeutic strategy to optimize inflammatory stimuli for triggering an anti-osteosarcoma macrophage response.
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http://dx.doi.org/10.1111/vco.12529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384208PMC
March 2020

Epidemiologic and survival trends in adult primary bone tumors of the spine.

Spine J 2019 12 12;19(12):1941-1949. Epub 2019 Jul 12.

Department of Orthopedics Surgery, Duke University Medical Center, Durham, NC, USA.

Background Context: Malignant primary spinal tumors are rare making it difficult to perform large studies comparing epidemiologic, survival, and treatment trends. We investigated the largest registry of primary bone tumors, the National Cancer Database (NCDB), to compare epidemiologic and survival trends among these tumors.

Purpose: To use the NCDB to describe current epidemiologic trends, treatment modalities, and overall survival rates in patients with chordomas, osteosarcomas, chondrosarcomas, and Ewing sarcomas of the mobile spine. The secondary objective was to determine prognostic factors that impact overall survival rates.

Study Design: Retrospective study.

Patient Sample: A total of 1,011 patients with primary bone tumors of the spine (377 chordomas, 223 chondrosarcomas, 278 Ewing sarcomas, and 133 osteosarcomas).

Outcome Measures: Five-year survival.

Methods: We reviewed the records of 1,011 patients in the NCDB from 2004 through 2015 with histologically confirmed primary osteosarcoma, chondrosarcoma, Ewing sarcoma, or chordoma of the spine. Demographic, clinical, and outcomes data were compiled and compared using chi-squared tests and ANOVA. Long-term survival was compared using the Kaplan-Meier method with statistical comparisons based on the log-rank test. Multivariate analysis was performed to determine survival determinants.

Results: Surgical resection was the primary mode of treatment for chondrosarcoma (90%), chordoma (84%), and osteosarcoma (80%). The treatment for Ewing sarcoma was multimodal involving chemotherapy, radiation therapy, and surgical resection. Five-year survival rates varied significantly with chordomas and chondrosarcomas having the greatest survival (70% and 69%), osteosarcomas having the worse survival (38%), and Ewing having intermediate 5-year survival at 62% (overall log-rank p<.0001). Multivariate analysis demonstrated significantly improved 5-year survival rates with younger age at diagnosis, private insurance status, lower comorbidity score, lower tumor grade, smaller tumor size, surgical resection, and negative surgical margin. Radiation therapy only improved survival for Ewing sarcoma.

Conclusions: This study provides the most comprehensive description of the epidemiologic, treatment, and survival trends of primary bone tumors of the mobile spine. Second, patient and tumor characteristics associated with improved 5-year survival were identified using a multivariate model.
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http://dx.doi.org/10.1016/j.spinee.2019.07.003DOI Listing
December 2019
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