Brian E Brigman

Duke University, Durham, North Carolina, United States

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Publications (55)172.86 Total impact

  • Julia D. Visgauss · William C. Eward · Brian E. Brigman
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    ABSTRACT: In the surgical management of solid tumors, adequacy of tumor resection has implications for local recurrence and survival. The standard method of intraoperative identification of tumor margin is frozen section pathologic analysis, which is time-consuming with potential for sampling error. Intraoperative tumor visualization has the potential to significantly improve surgical cancer care across disciplines, by guiding accuracy of biopsies, increasing adequacy of resections, directing adjuvant therapy, and even providing diagnostic information. We provide an outline of various methods of intraoperative tumor visualization developed to aid in the real-time assessment of tumor extent and adequacy of resection.
    No preview · Article · Jan 2016 · Orthopedic Clinics of North America
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    ABSTRACT: Local recurrence is a common cause of treatment failure for patients with solid tumors. Intraoperative detection of microscopic residual cancer in the tumor bed could be used to decrease the risk of a positive surgical margin, reduce rates of reexcision, and tailor adjuvant therapy. We used a protease-activated fluorescent imaging probe, LUM015, to detect cancer in vivo in a mouse model of soft tissue sarcoma (STS) and ex vivo in a first-in-human phase 1 clinical trial. In mice, intravenous injection of LUM015 labeled tumor cells, and residual fluorescence within the tumor bed predicted local recurrence. In 15 patients with STS or breast cancer, intravenous injection of LUM015 before surgery was well tolerated. Imaging of resected human tissues showed that fluorescence from tumor was significantly higher than fluorescence from normal tissues. LUM015 biodistribution, pharmacokinetic profiles, and metabolism were similar in mouse and human subjects. Tissue concentrations of LUM015 and its metabolites, including fluorescently labeled lysine, demonstrated that LUM015 is selectively distributed to tumors where it is activated by proteases. Experiments in mice with a constitutively active PEGylated fluorescent imaging probe support a model where tumor-selective probe distribution is a determinant of increased fluorescence in cancer. These co-clinical studies suggest that the tumor specificity of protease-activated imaging probes, such as LUM015, is dependent on both biodistribution and enzyme activity. Our first-in-human data support future clinical trials of LUM015 and other protease-sensitive probes.
    Full-text · Article · Jan 2016 · Science translational medicine
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    ABSTRACT: The treatment of soft tissue sarcoma (STS) generally involves tumor excision with a wide margin. Although advances in fluorescence imaging make real-time detection of cancer possible, removal is limited by the precision of the human eye and hand. Here, we describe a novel pulsed Nd:YAG laser ablation system that, when used in conjunction with a previously described molecular imaging system, can identify and ablate cancer in vivo. Mice with primary STS were injected with the protease-activatable probe LUM015 to label tumors. Resected tissues from the mice were then imaged and treated with the laser using the paired fluorescence-imaging/ laser ablation device, generating ablation clefts with sub-millimeter precision and minimal underlying tissue damage. Laser ablation was guided by fluorescence to target tumor tissues, avoiding normal structures. The selective ablation of tumor implants in vivo improved recurrence-free survival after tumor resection in a cohort of 14 mice compared to 12 mice that received no ablative therapy. This prototype system has the potential to be modified so that it can be used during surgery to improve recurrence-free survival in patients with cancer.
    Full-text · Article · Jan 2016 · Theranostics
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    R D Dodd · M Sachdeva · J K Mito · W C Eward · B E Brigman · Y Ma · L Dodd · Y Kim · D Lev · D G Kirsch
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    ABSTRACT: Approximately 30% of patients with soft-tissue sarcoma die from pulmonary metastases. The mechanisms that drive sarcoma metastasis are not well understood. Recently, we identified miR-182 as a driver of sarcoma metastasis in a primary mouse model of soft-tissue sarcoma. We also observed elevated miR-182 in a subset of primary human sarcomas that metastasized to the lungs. Here, we show that myogenic differentiation factors regulate miR-182 levels to contribute to metastasis in mouse models. We find that MyoD directly binds the miR-182 promoter to increase miR-182 expression. Furthermore, mechanistic studies revealed that Pax7 can promote sarcoma metastasis in vivo through MyoD-dependent regulation of pro-metastatic miR-182. Taken together, these results suggest that sarcoma metastasis can be partially controlled through Pax7/MyoD-dependent activation of miR-182 and provide insight into the role that myogenic transcription factors have in sarcoma progression.Oncogene advance online publication, 3 August 2015; doi:10.1038/onc.2015.252.
    Full-text · Article · Aug 2015 · Oncogene

  • No preview · Article · Aug 2015 · Cancer Research
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    Full-text · Article · Jul 2015 · Journal of Gastrointestinal Cancer
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    ABSTRACT: Objective. This study investigated patterns of utilization of radiation therapy (RT) and correlated this with overall survival by assessing patients with well-differentiated soft tissue sarcoma of the extremity (STS-E) in the National Cancer Database (NCDB). Methods. All patients diagnosed with well-differentiated STS-E between 1998 and 2006 were identified in the NCDB. Patients were stratified by use of surgery alone versus use of adjuvant RT after surgery and analyzed using multivariate analysis, Kaplan-Meier analysis, and propensity matching. Results. 2113 patients with well-differentiated STS-E were identified in the NCDB for inclusion with a mean follow-up time of 74 months. 69% of patients were treated with surgery alone, while 26% were treated with surgery followed by adjuvant RT. Patients undergoing amputation were less likely to receive adjuvant RT. There was no difference in overall survival between patients with well-differentiated STS treated with surgery alone and those patients who received adjuvant RT. Conclusions. In the United States, adjuvant RT is being utilized in a quarter of patients being treated for well-differentiated STS-E. While the use of adjuvant RT may be viewed as a means to facilitate limb salvage, this large national database review confirms no survival benefit, regardless of tumor size or margin status.
    Full-text · Article · Jun 2015 · Sarcoma
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    ABSTRACT: To compare the acute effects of radiofrequency (RF) ablation and cryoablation on the structural integrity of nontarget periarticular tissues that may be placed at risk during percutaneous bone ablation. RF ablation and cryoablation were separately performed on tendon, articular cartilage, and ligament in an ex vivo porcine model by using standard bone ablation protocols. Gross and histopathologic analysis was performed on cartilage and tendon (n = 6 for each treatment group, n = 5 controls). Tendon lengths were measured before and after ablation. Biomechanical tensile testing was performed on each ligament sample after ablation, with quantification of ultimate load at failure and linear stiffness (n = 7 ligaments in treatment and control groups). RF ablation and cryoablation injured chondrocytes within the ablation zones but caused minimal effects on gross and histologic cartilage architecture. Cryoablation resulted in minimal gross and histologic effects on tendon whereas RF ablation resulted in marked disruption of collagen fibers and significant longitudinal shortening (P = .002). Similarly, cryoablation did not alter ligament strength or stiffness compared with control, whereas RF ablation resulted in a significant decrease in tensile strength and stiffness compared with control and cryoablation samples (P < .001). Neither RF ablation nor cryoablation resulted in significant acute changes in cartilage architecture. However, RF ablation resulted in marked disruption of tendon architecture, tendon shortening, ligament weakening, and loss of ligament stiffness, whereas cryoablation had no significant effect on any of these parameters. These findings suggest that cryoablation may have fewer negative acute effects than RF ablation, although long-term outcomes are currently unknown. Copyright © 2015 SIR. Published by Elsevier Inc. All rights reserved.
    No preview · Article · Jun 2015 · Journal of vascular and interventional radiology: JVIR
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    ABSTRACT: Background: It is a consensus that radiation therapy (RT) should be applied for all large, deep, high-grade soft tissue sarcomas (STS). Therefore, we investigated the National Cancer Database (NCDB) to study how these guidelines are being followed, to determine what factors may be associated with the decision not to use RT, and to see whether there was an association of RT use and survival. Methods: We retrospectively analyzed localized high-grade STS patients in the NCDB from 1998 through 2006. They were further stratified into two groups: no radiation (NRT) group and radiation (RT) group. Then, long-term survival between the two groups was evaluated using the Kaplan-Meier (KM) method with comparisons based on the log-rank test. Multiple variables were analyzed between the two groups. Propensity matching was performed secondarily to minimize the influence of confounding variables. Results: A total of 3982 of 10,290 patients (37.8 %) did not receive RT and 6,308 patients (62.2 %) did receive RT. Patients in the NRT group were more likely to have a below-median education level (median 58.2 % vs. 60.7 %; p = 0.015) and a below-median income level (65.1 % vs. 68.6 %; p < 0.001). In addition, these patients lived farther from their treatment centers (20.2 vs. 14.8 miles, p = 0.002) and were more likely to be uninsured (5.3 % vs. 3.5 %, p < 0.001). They were less likely to receive a radical excision (55.2 % vs. 70.1 %; p < 0.001) and more likely to receive amputation (20.9 % vs. 3.3 %; p < 0.001). The 30-day mortality (1.2 % vs. 0.2 %; p < 0.001) and readmission rate (3.8 % vs. 2.8 %; p = 0.031) were higher for the NRT group. KM analysis showed that long-term survival for patients who did not receive RT was significantly lower, even after propensity score matching (p < 0.001). Conclusions: This large database review reveals a striking lack of utilization of RT to treat high-grade STS, which correlates with poorer survival even after propensity matching. Lower education and income levels and diminished access to medical care (insurance and distance to the facility) are associated with failing to receive RT.
    Full-text · Article · Jun 2015 · Annals of Surgical Oncology
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    ABSTRACT: Anterior cruciate ligament (ACL) injuries are one of the most common knee injuries, with over 100,000 ACL reconstructions performed in the United States every year. There are a number of graft options available for use in ACL repair. Hamstring tendon autografts are commonly used for ACL reconstruction. The advantages cited for autografts versus allografts are as follows: lower cost, no risk of immunological reactions, and better integration and remodeling. The healing response depends on the interplay between the bone and tendon in which collagen fiber continuity is re-established. This process is achieved by bony ingrowth of immature trabecular bone into immature, disorganized collagen fibers. Gradually, the collagen fibers reorganize into a parallel array until the tendo-osseous junction is re-established. Studies of the healing response involved in ACL autograft reconstruction have been well documented in animal studies, but most studies of the graft healing response in human patients have been limited to biopsy specimens. To our knowledge, there are no examples in the literature of the ACL graft healing response in the tibial and femoral tunnels of human whole knee specimens. Beynnon et al, in a previous study, performed biomechanical testing on a recovered human ACL graft but did not specifically examine the healing response. We report the case of a young male patient who subsequently required resection of his knee for osteosarcoma of the tibia 4 months after ACL reconstruction with a hamstring tendon autograft. The patient and his parents provided written informed consent for print and electronic publication of this case report.
    Full-text · Article · May 2015 · The American Journal of Sports Medicine

  • No preview · Conference Paper · Feb 2015
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    ABSTRACT: Castleman disease is a rare lymphoproliferative disorder of unknown etiology that most commonly presents as a mediastinal nodal mass or, in the extranodal form of the disease, a mass located in the mediastinum or retroperitoneum. It is exceptionally uncommon for Castleman disease to present in the extremities. We report a rare case of extranodal Castleman disease presenting as a muscular forearm mass. We compare our case with the seven other reported cases in which Castleman disease presented as an isolated soft tissue mass in the extremities.
    Full-text · Article · Jun 2014 · Skeletal Radiology
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    ABSTRACT: Skeletal reconstruction after large tumor resection is challenging. The free vascularized fibular graft (FVFG) offers the potential for rapid autograft incorporation as well as growing physeal transfer in pediatric patients. We retrospectively reviewed eleven pediatric patients treated with FVFG reconstructions of the upper extremity after tumor resection. Eight male and three female patients were identified, including four who underwent epiphyseal transfer. All eleven patients retained a functional salvaged limb. Nonunion and graft fracture were the most common complications relating to graft site (27%). Peroneal nerve palsy occurred in 4/11 patients, all of whom received epiphyseal transfer. Patients receiving epiphyseal transplant had a mean annual growth of 1.7 cm/year. Mean graft hypertrophy index increased by more than 10% in all cases. Although a high complication rate may be anticipated, the free vascularized fibula may be used to reconstruct large skeletal defects in the pediatric upper extremity after oncologic resection. Transferring the vascularized physis is a viable option when longitudinal growth is desired.
    Full-text · Article · Oct 2013 · Sarcoma
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    ABSTRACT: Free vascularized fibular transfer has become a standard procedure in upper extremity reconstruction after resection of osteogenic tumors. The authors present two rare pediatric cases of high-grade osteosarcoma resection of the proximal humerus. A free vascularized fibula autograft including the physis based on the anterior tibial artery and vein was used for reconstruction in a delayed (case 1) and immediate (case 2) approach. The main focus of the article is to describe the surgical technique, which is also presented in a series of intraoperative videos. Therapeutic, V.
    No preview · Article · Aug 2013 · Plastic and Reconstructive Surgery
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    Brian A Mata · William C Eward · Brian E Brigman
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    ABSTRACT: Synovial chondromatosis is a rare, benign, metaplastic condition in which synovial tissue becomes hyperplastic, and foci of cartilaginous metaplasia develop in the synovial membranes of joints, bursae, or tendon sheaths. Involvement is most commonly monoarticular. The large joints are most commonly affected, with the knee accounting for more than half of all cases. There are isolated reports of synovial chondromatosis occurring in the small joints of the wrist and hand. However, it is very uncommon for the disease to involve multiple different synovial structures. We report the case of a middle-aged man with pancarpal synovial chondromatosis with involvement of numerous bony, articular, and tenosynovial structures within the hand and wrist.
    Full-text · Article · Aug 2013 · American journal of orthopedics (Belle Mead, N.J.)
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    ABSTRACT: Tumor-induced osteomalacia is a paraneoplastic syndrome resulting in renal phosphate wasting and decreased bone mineralization. Phosphaturic mesenchymal tumors represent a rare etiology of tumor-induced osteomalacia. Nonspecific symptoms of fatigue, bone pain, and musculoskeletal weakness make the diagnosis elusive and lead to a delay in surgical treatment. In this case series, the following three questions were asked: (1) How do the clinical presentation and features of phosphaturic mesenchymal tumors delay the diagnosis? (2) What is the clinical course after surgical treatment of phosphaturic mesenchymal tumors? (3) How frequently do phosphaturic mesenchymal tumors recur and are there factors associated with recurrence? This study retrospectively reviewed the cases of five adults diagnosed and treated for phosphaturic mesenchymal tumors. Patients were identified through an internal orthopaedic oncology database with clinical, surgical, and histologic data obtained through a systematic chart review. Five patients presented with a long-standing history of osteomalacia, generalized fatigue, pain, and weakness before the diagnosis was reached at an average of 7.2 years (range, 2-12 years) after initial symptom onset. The diagnosis appeared to be delayed owing to the cryptic medical presentation, difficulty in locating tumor by imaging, and confirming histologic appearance. Two patients treated with wide surgical resection did not experience recurrence compared with three patients who did show recurrent signs and symptoms after marginal excision. A postoperative increase in fibroblast-derived growth factor-23 was associated with recurrent disease. Although uncommon, the diagnosis of phosphaturic mesenchymal tumor should be considered in any patient who presents with hypophosphaturic osteomalacia and no other physiologic cause. Definitive treatment is early, wide surgical resection.
    Full-text · Article · Jul 2013 · Clinical Orthopaedics and Related Research
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    ABSTRACT: Soft tissue sarcomas are rare cancers. They should be managed by a multidisciplinary team with experience caring for these diverse malignancies. Local control is frequently achieved with a combination of radiation therapy and surgery. This article reviews the data supporting the role of adjuvant radiotherapy in the care of patients with soft tissue sarcoma and describes the side effects of surgery and radiation therapy. Preoperative radiation therapy increases the risk of wound complication from surgery, but has fewer long-term side effects than postoperative radiation therapy. The timing of radiation therapy can be tailored to each patient.
    No preview · Article · Jul 2013 · Surgical Oncology Clinics of North America
  • Article: Bone cancer
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    ABSTRACT: Primary bone cancers are extremely rare neoplasms, accounting for fewer than 0.2% of all cancers. The evaluation and treatment of patients with bone cancers requires a multidisciplinary team of physicians, including musculoskeletal, medical, and radiation oncologists, and surgeons and radiologists with demonstrated expertise in the management of these tumors. Long-term surveillance and follow-up are necessary for the management of treatment late effects related to surgery, radiation therapy, and chemotherapy. These guidelines discuss the management of chordoma, giant cell tumor of the bone, and osteosarcoma.
    No preview · Article · Jun 2013
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    ABSTRACT: Purpose: Cathepsin-activated fluorescent probes can detect tumors in mice and in canine patients. We previously showed that these probes can detect microscopic residual sarcoma in the tumor bed of mice during gross total resection. Many patients with soft tissue sarcoma (STS) and other tumors undergo radiation therapy (RT) before surgery. This study assesses the effect of RT on the ability of cathepsin-activated probes to differentiate between normal and cancerous tissue. Methods and Materials: A genetically engineered mouse model of STS was used to generate primary hind limb sarcomas that were treated with hypofractionated RT. Mice were injected intravenously with cathepsin-activated fluorescent probes, and various tissues, including the tumor, were imaged using a hand-held imaging device. Resected tumor and normal muscle samples were harvested to assess cathepsin expression by Western blot. Uptake of activated probe was analyzed by flow cytometry and confocal microscopy. Parallel in vitro studies using mouse sarcoma cells were performed. Results: RT of primary STS in mice and mouse sarcoma cell lines caused no change in probe activation or cathepsin protease expression. Increasing radiation dose resulted in an upward trend in probe activation. Flow cytometry and immunofluorescence showed that a substantial proportion of probe-labeled cells were CD11b-positive tumor-associated immune cells. Conclusions: In this primary murine model of STS, RT did not affect the ability of cathepsin-activated probes to differentiate between tumor and normal muscle. Cathepsin-activated probes labeled tumor cells and tumor-associated macrophages. Our results suggest that it would be feasible to include patients who have received preoperative RT in clinical studies evaluating cathepsin-activated imaging probes.
    Full-text · Article · Feb 2013 · International journal of radiation oncology, biology, physics
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    ABSTRACT: Undifferentiated pleomorphic sarcoma (UPS) is one of the most common soft tissue malignancies. Patients with large, high grade sarcomas often develop fatal lung metastases. Understanding the mechanisms underlying sarcoma metastasis are needed to improve treatment of these patients. Micro-RNAs (miRNAs) are a class of small RNAs that post-transcriptionally regulate gene expression. Global alterations in miRNAs are frequently observed in a number of disease states including cancer. The signaling pathways that regulate miRNA biogenesis are beginning to emerge. To test the relevance of specific oncogenic mutations on miRNA biogenesis in sarcoma, we used primary soft tissue sarcomas expressing either Braf(V600E) or Kras(G12D) . We find that Braf(V600E) mutant tumors, which have increased MAPK signaling, have higher levels of mature miRNAs and enhanced miRNA processing. To investigate the relevance of oncogene dependent alterations in miRNA biogenesis, we introduce conditional mutations in Dicer and show that Dicer haploinsufficiency promotes the development of distant metastases in an oncogene dependent manner. These results demonstrate that a specific oncogenic mutation can cooperate with mutation in Dicer to promote tumor progression in vivo. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
    No preview · Article · Jan 2013 · The Journal of Pathology

Publication Stats

998 Citations
172.86 Total Impact Points

Institutions

  • 2004-2016
    • Duke University
      • Department of Surgery
      Durham, North Carolina, United States
  • 2003-2015
    • Duke University Medical Center
      • • Department of Surgery
      • • Department of Orthopaedic Surgery
      Durham, North Carolina, United States
  • 2002
    • Politeknik Kota Bharu
      Ketereh, Kelantan, Malaysia
  • 2000
    • Creighton University
      • Department of Surgery
      Omaha, Nebraska, United States
  • 1994-1996
    • University of North Carolina at Chapel Hill
      • • Department of Surgery
      • • Department of Orthopaedics
      North Carolina, United States