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Brigman, Brian Eugene

Positions:

Associate Professor of Orthopaedic Surgery

Orthopaedics
School of Medicine

Associate Professor of Pediatrics

Pediatrics
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1994

M.D. — University of North Carolina at Chapel Hill

Intern, Surgery

University of Nebraska at Lincoln

Resident, Orthopaedic Surgery

University of Nebraska at Lincoln

Fellow, Orthopaedic Oncology

Boston University

Grants:

Protocol Number: 14-03-PATHOLHUM-02

Administered By
Orthopaedics
AwardedBy
IlluminOss Medical, Inc.
Role
Principal Investigator
Start Date
April 01, 2015
End Date
March 31, 2018

Engineered imaging nanoparticles for real-time detection of cancer in the tumor bed

Administered By
Orthopaedics
AwardedBy
Lumicell Diagnostics
Role
Principal Investigator
Start Date
September 01, 2013
End Date
January 31, 2015

Publications:

Factors Influencing Orthopedic Surgery Residents' Choice of Subspecialty Fellowship

Authors
Kavolus, JJ; Matson, AP; Byrd, WA; Brigman, BE
MLA Citation
Kavolus, JJ, Matson, AP, Byrd, WA, and Brigman, BE. "Factors Influencing Orthopedic Surgery Residents' Choice of Subspecialty Fellowship." Orthopedics 40.5 (September 1, 2017): e820-e824.
Source
crossref
Published In
Orthopedics
Volume
40
Issue
5
Publish Date
2017
Start Page
e820
End Page
e824
DOI
10.3928/01477447-20170619-01

Vascularized Fibula-Based Physis Transfer: A Follow-Up Study of Longitudinal Bone Growth and Complications.

The vascularized free fibula epiphyseal transfer provides an option for the preservation of limb lengthening after resection of the proximal humerus in pediatric sarcoma patients. The purpose of this study was to provide a long-term follow-up of longitudinal growth patterns and outcomes after free fibula epiphyseal transfer in upper extremity reconstruction.A retrospective review of 4 patients who underwent free fibula epiphyseal transfer after oncologic resection of the proximal humerus for osteosarcoma was performed. Oncologic details that could affect outcomes were included in the review: primary tumor pathology, location of malignancy, and presence of recurrence. Details on the reconstruction included longitudinal growth of the flap from the time of implantation to the most recently available radiograph and postoperative complications. The length of the fibula over time was measured from the humeral head to the olecranon process.All patients were alive at the start of this study. The average longitudinal growth rate of the free fibula epiphyseal transfer was 0.54 ± 0.18 cm/y, and patients demonstrated satisfactory and consistent longitudinal bone growth and hypertrophy over time. All 4 patients suffered from a complication of postoperative fibula graft fracture, and 1 of 4 patients experienced unremitting peroneal nerve damage. All patients demonstrated normal wrist and hand motion with a normal arc of elbow flexion and extension.This study demonstrates that the vascularized fibula epiphyseal transfer offers the ability to preserve longitudinal limb growth and hypertrophy throughout adolescence.

Authors
Shammas, RL; Avashia, YJ; Farjat, AE; Catanzano, AA; Levin, LS; Eward, WC; Brigman, BE; Erdmann, D
MLA Citation
Shammas, RL, Avashia, YJ, Farjat, AE, Catanzano, AA, Levin, LS, Eward, WC, Brigman, BE, and Erdmann, D. "Vascularized Fibula-Based Physis Transfer: A Follow-Up Study of Longitudinal Bone Growth and Complications." Plastic and reconstructive surgery. Global open 5.5 (May 25, 2017): e1352-.
PMID
28607872
Source
epmc
Published In
Plastic and Reconstructive Surgery, Global Open
Volume
5
Issue
5
Publish Date
2017
Start Page
e1352
DOI
10.1097/gox.0000000000001352

Tumors of the Epiphyses.

Authors
Grimm, NL; Tainter, DM; Eward, WC; Brigman, BE
MLA Citation
Grimm, NL, Tainter, DM, Eward, WC, and Brigman, BE. "Tumors of the Epiphyses." JBJS reviews 5.5 (May 23, 2017): e4-.
PMID
28538290
Source
epmc
Published In
JBJS Reviews
Volume
5
Issue
5
Publish Date
2017
Start Page
e4
DOI
10.2106/jbjs.rvw.16.00080

The stability of the hip after the use of a proximal femoral endoprosthesis for oncological indications: analysis of variables relating to the patient and the surgical technique.

Instability of the hip is the most common mode of failure after reconstruction with a proximal femoral arthroplasty (PFA) using an endoprosthesis after excision of a tumour. Small studies report improved stability with capsular repair of the hip and other techniques, but these have not been investigated in a large series of patients. The aim of this study was to evaluate variables associated with the patient and the operation that affect post-operative stability. We hypothesised an association between capsular repair and stability.In a retrospective cohort study, we identified 527 adult patients who were treated with a PFA for tumours. Our data included demographics, the pathological diagnosis, the amount of resection of the abductor muscles, the techniques of reconstruction and the characteristics of the implant. We used regression analysis to compare patients with and without post-operative instability.A total of 20 patients out of 527 (4%) had instability which presented at a mean of 35 days (3 to 131) post-operatively. Capsular repair was not associated with a reduced rate of instability. Bivariate analysis showed that a posterolateral surgical approach (odds ratio (OR) 0.11, 95% confidence interval (CI) 0.02 to 0.86) and the type of implant (p = 0.046) had a significant association with reduced instability; age > 60 years predicted instability (OR 3.17, 95% CI 1.00 to 9.98). Multivariate analysis showed age > 60 years (OR 5.09, 95% CI 1.23 to 21.07), female gender (OR 1.73, 95% CI 1.04 to 2.89), a malignant primary bone tumour (OR 2.04, 95% CI 1.06 to 3.95), and benign condition (OR 5.56, 95% CI 1.35 to 22.90), but not metastatic disease or soft-tissue tumours, predicted instability, while a posterolateral approach (OR 0.09, 95% CI 0.01 to 0.53) was protective against instability. No instability occurred when a synthetic graft was used in 70 patients.Stability of the hip after PFA is influenced by variables associated with the patient, the pathology, the surgical technique and the implant. We did not find an association between capsular repair and improved stability. Extension of the tumour often dictates surgical technique; however, our results indicate that PFA using a posterolateral approach with a hemiarthroplasty and synthetic augment for soft-tissue repair confers the lowest risk of instability. Patients who are elderly, female, or with a primary benign or malignant bone tumour should be counselled about an increased risk of instability. Cite this article: Bone Joint J 2017;99-B:531-7.

Authors
Henderson, ER; Keeney, BJ; Pala, E; Funovics, PT; Eward, WC; Groundland, JS; Ehrlichman, LK; Puchner, SSE; Brigman, BE; Ready, JE; Temple, HT; Ruggieri, P; Windhager, R; Letson, GD; Hornicek, FJ
MLA Citation
Henderson, ER, Keeney, BJ, Pala, E, Funovics, PT, Eward, WC, Groundland, JS, Ehrlichman, LK, Puchner, SSE, Brigman, BE, Ready, JE, Temple, HT, Ruggieri, P, Windhager, R, Letson, GD, and Hornicek, FJ. "The stability of the hip after the use of a proximal femoral endoprosthesis for oncological indications: analysis of variables relating to the patient and the surgical technique." The bone & joint journal 99-B.4 (April 2017): 531-537.
PMID
28385944
Source
epmc
Published In
Bone and Joint Journal
Volume
99-B
Issue
4
Publish Date
2017
Start Page
531
End Page
537
DOI
10.1302/0301-620x.99b4.bjj-2016-0960.r1

NCCN Guidelines Insights: Bone Cancer, Version 2.2017.

The NCCN Guidelines for Bone Cancer provide interdisciplinary recommendations for treating chordoma, chondrosarcoma, giant cell tumor of bone, Ewing sarcoma, and osteosarcoma. These NCCN Guidelines Insights summarize the NCCN Bone Cancer Panel's guideline recommendations for treating Ewing sarcoma. The data underlying these treatment recommendations are also discussed.

Authors
Biermann, JS; Chow, W; Reed, DR; Lucas, D; Adkins, DR; Agulnik, M; Benjamin, RS; Brigman, B; Budd, GT; Curry, WT; Didwania, A; Fabbri, N; Hornicek, FJ; Kuechle, JB; Lindskog, D; Mayerson, J; McGarry, SV; Million, L; Morris, CD; Movva, S; O'Donnell, RJ; Randall, RL; Rose, P; Santana, VM; Satcher, RL; Schwartz, H; Siegel, HJ; Thornton, K; Villalobos, V; Bergman, MA; Scavone, JL
MLA Citation
Biermann, JS, Chow, W, Reed, DR, Lucas, D, Adkins, DR, Agulnik, M, Benjamin, RS, Brigman, B, Budd, GT, Curry, WT, Didwania, A, Fabbri, N, Hornicek, FJ, Kuechle, JB, Lindskog, D, Mayerson, J, McGarry, SV, Million, L, Morris, CD, Movva, S, O'Donnell, RJ, Randall, RL, Rose, P, Santana, VM, Satcher, RL, Schwartz, H, Siegel, HJ, Thornton, K, Villalobos, V, Bergman, MA, and Scavone, JL. "NCCN Guidelines Insights: Bone Cancer, Version 2.2017." Journal of the National Comprehensive Cancer Network : JNCCN 15.2 (February 2017): 155-167.
PMID
28188186
Source
epmc
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
15
Issue
2
Publish Date
2017
Start Page
155
End Page
167
DOI
10.6004/jnccn.2017.0017

An NLRP3 Mutation Causes Arthropathy and Osteoporosis in Humanized Mice.

The NLRP3 inflammasome plays a critical role in host defense by facilitating caspase I activation and maturation of IL-1β and IL-18, whereas dysregulation of inflammasome activity results in autoinflammatory disease. Factors regulating human NLRP3 activity that contribute to the phenotypic heterogeneity of NLRP3-related diseases have largely been inferred from the study of Nlrp3 mutant mice. By generating a mouse line in which the NLRP3 locus is humanized by syntenic replacement, we show the functioning of the human NLRP3 proteins in vivo, demonstrating the ability of the human inflammasome to orchestrate immune reactions in response to innate stimuli. Humanized mice expressing disease-associated mutations develop normally but display acute sensitivity to endotoxin and develop progressive and debilitating arthritis characterized by granulocytic infiltrates, elevated cytokines, erosion of bones, and osteoporosis. This NLRP3-dependent arthritis model provides a platform for testing therapeutic reagents targeting the human inflammasome.

Authors
Snouwaert, JN; Nguyen, M; Repenning, PW; Dye, R; Livingston, EW; Kovarova, M; Moy, SS; Brigman, BE; Bateman, TA; Ting, JP-Y; Koller, BH
MLA Citation
Snouwaert, JN, Nguyen, M, Repenning, PW, Dye, R, Livingston, EW, Kovarova, M, Moy, SS, Brigman, BE, Bateman, TA, Ting, JP-Y, and Koller, BH. "An NLRP3 Mutation Causes Arthropathy and Osteoporosis in Humanized Mice." Cell reports 17.11 (December 2016): 3077-3088.
PMID
27974218
Source
epmc
Published In
Cell Reports
Volume
17
Issue
11
Publish Date
2016
Start Page
3077
End Page
3088
DOI
10.1016/j.celrep.2016.11.052

Simultaneous Primary Presacral Myelolipomas: Case Report and Review of the Literature.

Authors
Lazarides, AL; Scott, EJ; Cardona, DM; Blazer, DG; Brigman, BE; Eward, WC
MLA Citation
Lazarides, AL, Scott, EJ, Cardona, DM, Blazer, DG, Brigman, BE, and Eward, WC. "Simultaneous Primary Presacral Myelolipomas: Case Report and Review of the Literature." Journal of gastrointestinal cancer 47.3 (September 2016): 331-335. (Review)
PMID
26164122
Source
epmc
Published In
Journal of Gastrointestinal Cancer
Volume
47
Issue
3
Publish Date
2016
Start Page
331
End Page
335
DOI
10.1007/s12029-015-9749-5

A Novel Imaging System Distinguishes Neoplastic from Normal Tissue During Resection of Soft Tissue Sarcomas and Mast Cell Tumors in Dogs.

To assess the ability of a novel imaging system designed for intraoperative detection of residual cancer in tumor beds to distinguish neoplastic from normal tissue in dogs undergoing resection of soft tissue sarcoma (STS) and mast cell tumor (MCT).Non-randomized prospective clinical trial.12 dogs with STS and 7 dogs with MCT.A fluorescent imaging agent that is activated by proteases in vivo was administered to the dogs 4-6 or 24-26 hours before tumor resection. During surgery, a handheld imaging device was used to measure fluorescence intensity within the cancerous portion of the resected specimen and determine an intensity threshold for subsequent identification of cancer. Selected areas within the resected specimen and tumor bed were then imaged, and biopsies (n=101) were obtained from areas that did or did not have a fluorescence intensity exceeding the threshold. Results of intraoperative fluorescence and histology were compared.The imaging system correctly distinguished cancer from normal tissue in 93/101 biopsies (92%). Using histology as the reference, the sensitivity and specificity of the imaging system for identification of cancer in biopsies were 92% and 92%, respectively. There were 10/19 (53%) dogs which exhibited transient facial erythema soon after injection of the imaging agent which responded to but was not consistently prevented by intravenous diphenhydramine.A fluorescence-based imaging system designed for intraoperative use can distinguish canine soft tissue sarcoma (STS) and mast cell tumor (MCT) tissue from normal tissue with a high degree of accuracy. The system has potential to assist surgeons in assessing the adequacy of tumor resections during surgery, potentially reducing the risk of local tumor recurrence. Although responsive to antihistamines, the risk of hypersensitivity needs to be considered in light of the potential benefits of this imaging system in dogs.

Authors
Bartholf DeWitt, S; Eward, WC; Eward, CA; Lazarides, AL; Whitley, MJ; Ferrer, JM; Brigman, BE; Kirsch, DG; Berg, J
MLA Citation
Bartholf DeWitt, S, Eward, WC, Eward, CA, Lazarides, AL, Whitley, MJ, Ferrer, JM, Brigman, BE, Kirsch, DG, and Berg, J. "A Novel Imaging System Distinguishes Neoplastic from Normal Tissue During Resection of Soft Tissue Sarcomas and Mast Cell Tumors in Dogs." Veterinary surgery : VS 45.6 (August 2016): 715-722.
PMID
27281113
Source
epmc
Published In
Veterinary Surgery
Volume
45
Issue
6
Publish Date
2016
Start Page
715
End Page
722
DOI
10.1111/vsu.12487

Angiomatoid fibrous histiocytoma: novel MR imaging findings.

To describe novel MR imaging features, and clinical characteristics of soft tissue angiomatoid fibrous histiocytoma (AFH) at presentation, local recurrence, and metastases.We described the MRI findings of six cases of histologically proven AFH. Pathologic findings, clinical presentation, and outcome were reviewed.Lesions were primarily cystic. At initial presentation, tumors were surrounded by low signal intensity fibrous pseudocapsule. High signal intensity consistent with the lymphoplasmacytic infiltrate was seen in T2-weighted and post-contrast images as a rim over the hypointense pseudocapsule (double rim sign). High signal intensity infiltrating tumoral cords extended into adjacent tissues, through pseudocapsular defects on T2-weighted and post-contrast images. The cystic component and tumor cell nodularity were demonstrated at post-contrast images. Clinically, lesions were often thought to be benign, underwent marginal resection, developed local recurrence, and one developed second recurrence consisting of metastases. Recurrent tumors appeared as multiple masses, misinterpreted as post-surgical changes. An intramuscular recurrence demonstrated double rim and infiltrating margin.A predominantly well-circumscribed, primarily cystic mass with double-rim and marginal infiltration on MRI suggests the possibility of AFH, in particular in child or young adult. Inclusion of these novel observations in AFH differential diagnosis may have a significant impact on treatment and prevention of recurrence.

Authors
Martinez, SJ; Moreno, CC; Vinson, EN; Dodd, LG; Brigman, BE
MLA Citation
Martinez, SJ, Moreno, CC, Vinson, EN, Dodd, LG, and Brigman, BE. "Angiomatoid fibrous histiocytoma: novel MR imaging findings." Skeletal radiology 45.5 (May 2016): 661-670.
PMID
26919861
Source
epmc
Published In
Skeletal Radiology
Volume
45
Issue
5
Publish Date
2016
Start Page
661
End Page
670
DOI
10.1007/s00256-016-2344-4

Synovial Chondromatosis.

Authors
Neumann, JA; Garrigues, GE; Brigman, BE; Eward, WC
MLA Citation
Neumann, JA, Garrigues, GE, Brigman, BE, and Eward, WC. "Synovial Chondromatosis." JBJS reviews 4.5 (May 2016).
PMID
27490219
Source
epmc
Published In
JBJS Reviews
Volume
4
Issue
5
Publish Date
2016
DOI
10.2106/jbjs.rvw.o.00054

Myogenic transcription factors regulate pro-metastatic miR-182.

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.

Authors
Dodd, RD; Sachdeva, M; Mito, JK; Eward, WC; Brigman, BE; Ma, Y; Dodd, L; Kim, Y; Lev, D; Kirsch, DG
MLA Citation
Dodd, RD, Sachdeva, M, Mito, JK, Eward, WC, Brigman, BE, Ma, Y, Dodd, L, Kim, Y, Lev, D, and Kirsch, DG. "Myogenic transcription factors regulate pro-metastatic miR-182." Oncogene 35.14 (April 2016): 1868-1875.
PMID
26234681
Source
epmc
Published In
Oncogene: Including Oncogene Reviews
Volume
35
Issue
14
Publish Date
2016
Start Page
1868
End Page
1875
DOI
10.1038/onc.2015.252

Successful Translation of Fluorescence Navigation During Oncologic Surgery: A Consensus Report.

Navigation with fluorescence guidance has emerged in the last decade as a promising strategy to improve the efficacy of oncologic surgery. To achieve routine clinical use, the onus is on the surgical community to objectively assess the value of this technique. This assessment may facilitate both Food and Drug Administration approval of new optical imaging agents and reimbursement for the imaging procedures. It is critical to characterize fluorescence-guided procedural benefits over existing practices and to elucidate both the costs and the safety risks. This report is the result of a meeting of the International Society of Image Guided Surgery (www.isigs.org) on February 6, 2015, in Miami, Florida, and reflects a consensus of the participants' opinions. Our objective was to critically evaluate the imaging platform technology and optical imaging agents and to make recommendations for successful clinical trial development of this highly promising approach in oncologic surgery.

Authors
Rosenthal, EL; Warram, JM; de Boer, E; Basilion, JP; Biel, MA; Bogyo, M; Bouvet, M; Brigman, BE; Colson, YL; DeMeester, SR; Gurtner, GC; Ishizawa, T; Jacobs, PM; Keereweer, S; Liao, JC; Nguyen, QT; Olson, JM; Paulsen, KD; Rieves, D; Sumer, BD; Tweedle, MF; Vahrmeijer, AL; Weichert, JP; Wilson, BC; Zenn, MR; Zinn, KR; van Dam, GM
MLA Citation
Rosenthal, EL, Warram, JM, de Boer, E, Basilion, JP, Biel, MA, Bogyo, M, Bouvet, M, Brigman, BE, Colson, YL, DeMeester, SR, Gurtner, GC, Ishizawa, T, Jacobs, PM, Keereweer, S, Liao, JC, Nguyen, QT, Olson, JM, Paulsen, KD, Rieves, D, Sumer, BD, Tweedle, MF, Vahrmeijer, AL, Weichert, JP, Wilson, BC, Zenn, MR, Zinn, KR, and van Dam, GM. "Successful Translation of Fluorescence Navigation During Oncologic Surgery: A Consensus Report." Journal of nuclear medicine : official publication, Society of Nuclear Medicine 57.1 (January 2016): 144-150.
PMID
26449839
Source
epmc
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
57
Issue
1
Publish Date
2016
Start Page
144
End Page
150
DOI
10.2967/jnumed.115.158915

Innovations in Intraoperative Tumor Visualization.

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.

Authors
Visgauss, JD; Eward, WC; Brigman, BE
MLA Citation
Visgauss, JD, Eward, WC, and Brigman, BE. "Innovations in Intraoperative Tumor Visualization." The Orthopedic clinics of North America 47.1 (January 2016): 253-264. (Review)
PMID
26614939
Source
epmc
Published In
Orthopedic Clinics of North America
Volume
47
Issue
1
Publish Date
2016
Start Page
253
End Page
264
DOI
10.1016/j.ocl.2015.08.023

A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer.

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.

Authors
Whitley, MJ; Cardona, DM; Lazarides, AL; Spasojevic, I; Ferrer, JM; Cahill, J; Lee, C-L; Snuderl, M; Blazer, DG; Hwang, ES; Greenup, RA; Mosca, PJ; Mito, JK; Cuneo, KC; Larrier, NA; O'Reilly, EK; Riedel, RF; Eward, WC; Strasfeld, DB; Fukumura, D; Jain, RK; Lee, WD; Griffith, LG; Bawendi, MG; Kirsch, DG; Brigman, BE
MLA Citation
Whitley, MJ, Cardona, DM, Lazarides, AL, Spasojevic, I, Ferrer, JM, Cahill, J, Lee, C-L, Snuderl, M, Blazer, DG, Hwang, ES, Greenup, RA, Mosca, PJ, Mito, JK, Cuneo, KC, Larrier, NA, O'Reilly, EK, Riedel, RF, Eward, WC, Strasfeld, DB, Fukumura, D, Jain, RK, Lee, WD, Griffith, LG, Bawendi, MG, Kirsch, DG, and Brigman, BE. "A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer." Science translational medicine 8.320 (January 2016): 320ra4-.
PMID
26738797
Source
epmc
Published In
Science Translational Medicine
Volume
8
Issue
320
Publish Date
2016
Start Page
320ra4
DOI
10.1126/scitranslmed.aad0293

A Fluorescence-Guided Laser Ablation System for Removal of Residual Cancer in a Mouse Model of Soft Tissue Sarcoma.

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.

Authors
Lazarides, AL; Whitley, MJ; Strasfeld, DB; Cardona, DM; Ferrer, JM; Mueller, JL; Fu, HL; Bartholf DeWitt, S; Brigman, BE; Ramanujam, N; Kirsch, DG; Eward, WC
MLA Citation
Lazarides, AL, Whitley, MJ, Strasfeld, DB, Cardona, DM, Ferrer, JM, Mueller, JL, Fu, HL, Bartholf DeWitt, S, Brigman, BE, Ramanujam, N, Kirsch, DG, and Eward, WC. "A Fluorescence-Guided Laser Ablation System for Removal of Residual Cancer in a Mouse Model of Soft Tissue Sarcoma." Theranostics 6.2 (January 2016): 155-166.
Website
http://hdl.handle.net/10161/13883
PMID
26877775
Source
epmc
Published In
Theranostics
Volume
6
Issue
2
Publish Date
2016
Start Page
155
End Page
166
DOI
10.7150/thno.13536

The use of radiation therapy in localized high-grade soft tissue sarcoma and potential impact on survival.

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.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.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).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.

Authors
Hou, C-H; Lazarides, AL; Speicher, PJ; Nussbaum, DP; Blazer, DG; Kirsch, DG; Brigman, BE; Eward, WC
MLA Citation
Hou, C-H, Lazarides, AL, Speicher, PJ, Nussbaum, DP, Blazer, DG, Kirsch, DG, Brigman, BE, and Eward, WC. "The use of radiation therapy in localized high-grade soft tissue sarcoma and potential impact on survival." Annals of surgical oncology 22.9 (September 2015): 2831-2838.
PMID
26040605
Source
epmc
Published In
Annals of Surgical Oncology
Volume
22
Issue
9
Publish Date
2015
Start Page
2831
End Page
2838
DOI
10.1245/s10434-015-4639-4

Histological Evaluation of Tendon-Bone Healing of an Anterior Cruciate Ligament Hamstring Graft in a 14-Year-Old Boy.

Authors
Lazarides, AL; Eward, WC; Green, K; Cardona, DM; Brigman, BE; Taylor, DC
MLA Citation
Lazarides, AL, Eward, WC, Green, K, Cardona, DM, Brigman, BE, and Taylor, DC. "Histological Evaluation of Tendon-Bone Healing of an Anterior Cruciate Ligament Hamstring Graft in a 14-Year-Old Boy." The American journal of sports medicine 43.8 (August 2015): 1935-1940.
PMID
25968884
Source
epmc
Published In
American Journal of Sports Medicine
Volume
43
Issue
8
Publish Date
2015
Start Page
1935
End Page
1940
DOI
10.1177/0363546515584040

Comparison of Acute Histologic and Biomechanical Effects of Radiofrequency Ablation and Cryoablation on Periarticular Structures in a Swine Model.

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.

Authors
Vikingstad, EM; de Ridder, GG; Glisson, RR; Cardona, DM; DiPalma, D; Eward, WC; Brigman, BE; Nelson, RC; Kim, CY
MLA Citation
Vikingstad, EM, de Ridder, GG, Glisson, RR, Cardona, DM, DiPalma, D, Eward, WC, Brigman, BE, Nelson, RC, and Kim, CY. "Comparison of Acute Histologic and Biomechanical Effects of Radiofrequency Ablation and Cryoablation on Periarticular Structures in a Swine Model." Journal of vascular and interventional radiology : JVIR 26.8 (August 2015): 1221-1228.e1.
PMID
26065927
Source
epmc
Published In
JVIR: Journal of Vascular and Interventional Radiology
Volume
26
Issue
8
Publish Date
2015
Start Page
1221
End Page
1228.e1
DOI
10.1016/j.jvir.2015.04.013

A Phase I Clinical Trial of LUM015: A Protease-activated Fluorescent Imaging Agent to Detect Cancer during Surgery

Authors
Whitley, MJ; Cardona, DM; Blazer, DG; Hwang, E; Greenup, RA; Mosca, PJ; Cahill, J; Mito, JK; Cuneo, KC; Larrier, N; O'Reilly, E; Spasojevic, I; Riedel, RF; Eward, WC; Griffith, LG; Bawendi, MG; Kirsch, DG; Brigman, BE
MLA Citation
Whitley, MJ, Cardona, DM, Blazer, DG, Hwang, E, Greenup, RA, Mosca, PJ, Cahill, J, Mito, JK, Cuneo, KC, Larrier, N, O'Reilly, E, Spasojevic, I, Riedel, RF, Eward, WC, Griffith, LG, Bawendi, MG, Kirsch, DG, and Brigman, BE. "A Phase I Clinical Trial of LUM015: A Protease-activated Fluorescent Imaging Agent to Detect Cancer during Surgery." February 2015.
Source
wos-lite
Published In
Annals of Surgical Oncology
Volume
22
Publish Date
2015
Start Page
S11
End Page
S12

The Use of Radiation Therapy in Well-Differentiated Soft Tissue Sarcoma of the Extremities: An NCDB Review.

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.

Authors
Lazarides, AL; Eward, WC; Speicher, PJ; Hou, C-H; Nussbaum, DP; Green, C; Blazer, DG; Kirsch, DG; Brigman, BE
MLA Citation
Lazarides, AL, Eward, WC, Speicher, PJ, Hou, C-H, Nussbaum, DP, Green, C, Blazer, DG, Kirsch, DG, and Brigman, BE. "The Use of Radiation Therapy in Well-Differentiated Soft Tissue Sarcoma of the Extremities: An NCDB Review." Sarcoma 2015 (January 2015): 186581-.
PMID
26064077
Source
epmc
Published In
Sarcoma
Volume
2015
Publish Date
2015
Start Page
186581
DOI
10.1155/2015/186581

Extranodal Castleman disease of the extremities: a case report and review of the literature.

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.

Authors
Eward, WC; DeWitt, SB; Brigman, BE; Kontogeorgakos, V; Lagoo, AS
MLA Citation
Eward, WC, DeWitt, SB, Brigman, BE, Kontogeorgakos, V, and Lagoo, AS. "Extranodal Castleman disease of the extremities: a case report and review of the literature." Skeletal radiology 43.11 (November 2014): 1627-1631. (Review)
PMID
24970669
Source
epmc
Published In
Skeletal Radiology
Volume
43
Issue
11
Publish Date
2014
Start Page
1627
End Page
1631
DOI
10.1007/s00256-014-1945-z

A phase I study of the safety and activation of a cathepsin-activalable fluorescent cancer-specific probe LUM015.

Authors
Whitley, MJ; Cardona, DM; Blazer, DG; Hwang, SE; Mosca, PJ; Cahill, J; Ferrer, JM; Strasfeld, DB; Mlto, JK; Cuneo, KC; Lanier, N; Williams, O; Spasojevic, I; Riedel, RF; Eward, W; Lee, WD; Griffith, LG; Bawendi, M; Kirsch, DG; Brigman, BE
MLA Citation
Whitley, MJ, Cardona, DM, Blazer, DG, Hwang, SE, Mosca, PJ, Cahill, J, Ferrer, JM, Strasfeld, DB, Mlto, JK, Cuneo, KC, Lanier, N, Williams, O, Spasojevic, I, Riedel, RF, Eward, W, Lee, WD, Griffith, LG, Bawendi, M, Kirsch, DG, and Brigman, BE. "A phase I study of the safety and activation of a cathepsin-activalable fluorescent cancer-specific probe LUM015." May 20, 2014.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
32
Issue
15
Publish Date
2014

The phosphaturic mesenchymal tumor: why is definitive diagnosis and curative surgery often delayed?

BACKGROUND: 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. QUESTIONS/PURPOSES: 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? METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Authors
Ledford, CK; Zelenski, NA; Cardona, DM; Brigman, BE; Eward, WC
MLA Citation
Ledford, CK, Zelenski, NA, Cardona, DM, Brigman, BE, and Eward, WC. "The phosphaturic mesenchymal tumor: why is definitive diagnosis and curative surgery often delayed?." Clin Orthop Relat Res 471.11 (November 2013): 3618-3625.
PMID
23868423
Source
pubmed
Published In
Clinical Orthopaedics and Related Research ®
Volume
471
Issue
11
Publish Date
2013
Start Page
3618
End Page
3625
DOI
10.1007/s11999-013-3178-1

Vascularized fibula-based physis transfer for pediatric proximal humerus reconstruction.

UNLABELLED: 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. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

Authors
Erdmann, D; Garcia, RM; Blueschke, G; Brigman, BE; Levin, LS
MLA Citation
Erdmann, D, Garcia, RM, Blueschke, G, Brigman, BE, and Levin, LS. "Vascularized fibula-based physis transfer for pediatric proximal humerus reconstruction." Plast Reconstr Surg 132.2 (August 2013): 281e-287e.
PMID
23897356
Source
pubmed
Published In
Plastic and Reconstructive Surgery
Volume
132
Issue
2
Publish Date
2013
Start Page
281e
End Page
287e
DOI
10.1097/PRS.0b013e31829589fb

Pancarpal synovial and tenosynovial chondromatosis in a 65-year-old man: a highly unusual presentation of a common condition.

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.

Authors
Mata, BA; Eward, WC; Brigman, BE
MLA Citation
Mata, BA, Eward, WC, and Brigman, BE. "Pancarpal synovial and tenosynovial chondromatosis in a 65-year-old man: a highly unusual presentation of a common condition." Am J Orthop (Belle Mead NJ) 42.8 (August 2013): E60-E63. (Review)
PMID
24078960
Source
pubmed
Published In
American Journal of Orthopedics
Volume
42
Issue
8
Publish Date
2013
Start Page
E60
End Page
E63

Practical radiation oncology for extremity sarcomas.

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.

Authors
Larrier, NA; Kirsch, DG; Riedel, RF; Levinson, H; Eward, WC; Brigman, BE
MLA Citation
Larrier, NA, Kirsch, DG, Riedel, RF, Levinson, H, Eward, WC, and Brigman, BE. "Practical radiation oncology for extremity sarcomas." Surg Oncol Clin N Am 22.3 (July 2013): 433-443. (Review)
PMID
23622072
Source
pubmed
Published In
Surgical Oncology Clinics of North America
Volume
22
Issue
3
Publish Date
2013
Start Page
433
End Page
443
DOI
10.1016/j.soc.2013.02.004

Imaging primary mouse sarcomas after radiation therapy using cathepsin-activatable fluorescent imaging agents.

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.

Authors
Cuneo, KC; Mito, JK; Javid, MP; Ferrer, JM; Kim, Y; Lee, WD; Bawendi, MG; Brigman, BE; Kirsch, DG
MLA Citation
Cuneo, KC, Mito, JK, Javid, MP, Ferrer, JM, Kim, Y, Lee, WD, Bawendi, MG, Brigman, BE, and Kirsch, DG. "Imaging primary mouse sarcomas after radiation therapy using cathepsin-activatable fluorescent imaging agents." Int J Radiat Oncol Biol Phys 86.1 (May 1, 2013): 136-142.
PMID
23391816
Source
pubmed
Published In
International Journal of Radiation: Oncology - Biology - Physics
Volume
86
Issue
1
Publish Date
2013
Start Page
136
End Page
142
DOI
10.1016/j.ijrobp.2012.12.007

A novel imaging system permits real-time in vivo tumor bed assessment after resection of naturally occurring sarcomas in dogs.

Treatment of soft tissue sarcoma (STS) includes complete tumor excision. However, in some patients, residual sarcoma cells remain in the tumor bed. We previously described a novel hand-held imaging device prototype that uses molecular imaging to detect microscopic residual cancer in mice during surgery.To test this device in a clinical trial of dogs with naturally occurring sarcomas, we asked: (1) Are any adverse clinical or laboratory effects observed after intravenous administration of the fluorescent probes? (2) Do canine sarcomas exhibit fluorescence after administration of the cathepsin-activated probe? (3) Is the tumor-to-background ratio sufficient to distinguish tumor from tumor bed? And (4) can residual fluorescence be detected in the tumor bed during surgery and does this correlate with a positive margin?We studied nine dogs undergoing treatment for 10 STS or mast cell tumors. Dogs received an intravenous injection of VM249, a fluorescent probe that becomes optically active in the presence of cathepsin proteases. After injection, tumors were removed by wide resection. The tumor bed was imaged using the novel imaging device to search for residual fluorescence. We determined correlations between tissue fluorescence and histopathology, cathepsin protease expression, and development of recurrent disease. Minimum followup was 9 months (mean, 12 months; range, 9-15 months).Fluorescence was apparent from all 10 tumors and ranged from 3 × 10(7) to 1 × 10(9) counts/millisecond/cm(2). During intraoperative imaging, normal skeletal muscle showed no residual fluorescence. Histopathologic assessment of surgical margins correlated with intraoperative imaging in nine of 10 cases; in the other case, there was no residual fluorescence, but tumor was found at the margin on histologic examination. No animals had recurrent disease at 9 to 15 months.These initial findings suggest this imaging system might be useful to intraoperatively detect residual tumor after wide resections.The ability to assess the tumor bed intraoperatively for residual disease has the potential to improve local control.

Authors
Eward, WC; Mito, JK; Eward, CA; Carter, JE; Ferrer, JM; Kirsch, DG; Brigman, BE
MLA Citation
Eward, WC, Mito, JK, Eward, CA, Carter, JE, Ferrer, JM, Kirsch, DG, and Brigman, BE. "A novel imaging system permits real-time in vivo tumor bed assessment after resection of naturally occurring sarcomas in dogs." Clinical Orthopaedics and Related Research 471.3 (March 2013): 834-842.
PMID
22972654
Source
epmc
Published In
Clinical Orthopaedics and Related Research ®
Volume
471
Issue
3
Publish Date
2013
Start Page
834
End Page
842
DOI
10.1007/s11999-012-2560-8

Oncogene-dependent control of miRNA biogenesis and metastatic progression in a model of undifferentiated pleomorphic sarcoma.

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 is 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 signalling pathways that regulate miRNA biogenesis are beginning to emerge. To test the relevance of specific oncogenic mutations in miRNA biogenesis in sarcoma, we used primary soft tissue sarcomas expressing either Braf(V600E) or Kras(G12D). We found that Braf(V600E) mutant tumours, which have increased MAPK signalling, have higher levels of mature miRNAs and enhanced miRNA processing. To investigate the relevance of oncogene-dependent alterations in miRNA biogenesis, we introduced conditional mutations in Dicer and showed 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 tumour progression in vivo.

Authors
Mito, JK; Min, HD; Ma, Y; Carter, JE; Brigman, BE; Dodd, L; Dankort, D; McMahon, M; Kirsch, DG
MLA Citation
Mito, JK, Min, HD, Ma, Y, Carter, JE, Brigman, BE, Dodd, L, Dankort, D, McMahon, M, and Kirsch, DG. "Oncogene-dependent control of miRNA biogenesis and metastatic progression in a model of undifferentiated pleomorphic sarcoma." The Journal of pathology 229.1 (January 2013): 132-140.
PMID
22951975
Source
epmc
Published In
The Journal of Pathology
Volume
229
Issue
1
Publish Date
2013
Start Page
132
End Page
140
DOI
10.1002/path.4099

Oncogene-dependent control of miRNA biogenesis and metastatic progression in a model of undifferentiated pleomorphic sarcoma

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 is 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 signalling pathways that regulate miRNA biogenesis are beginning to emerge. To test the relevance of specific oncogenic mutations in miRNA biogenesis in sarcoma, we used primary soft tissue sarcomas expressing either BrafV600E or KrasG12D. We found that Braf V600E mutant tumours, which have increased MAPK signalling, have higher levels of mature miRNAs and enhanced miRNA processing. To investigate the relevance of oncogene-dependent alterations in miRNA biogenesis, we introduced conditional mutations in Dicer and showed 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 tumour progression in vivo.Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Authors
Mito, JK; Min, HD; Ma, Y; Carter, JE; Brigman, BE; Dodd, L; Dankort, D; McMahon, M; Kirsch, DG
MLA Citation
Mito, JK, Min, HD, Ma, Y, Carter, JE, Brigman, BE, Dodd, L, Dankort, D, McMahon, M, and Kirsch, DG. "Oncogene-dependent control of miRNA biogenesis and metastatic progression in a model of undifferentiated pleomorphic sarcoma." Journal of Pathology 229.1 (2013): 132-140.
Source
scival
Published In
The Journal of Pathology
Volume
229
Issue
1
Publish Date
2013
Start Page
132
End Page
140
DOI
10.1002/path.4099

Bone Cancer: Clinical practice guidelines in oncology

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. Copyright © 2013 by the National Comprehensive Cancer Network.

Authors
Biermann, JS; Adkins, DR; Agulnik, M; Benjamin, RS; Brigman, B; Butrynski, JE; Cheong, D; Chow, W; Curry, WT; Frassica, DA; Frassica, FJ; Hande, KR; Hornicek, FJ; Jones, RL; Mayerson, J; McGarry, SV; McGrath, B; Morris, CD; O'donnell, RJ; Randall, RL; Santana, VM; Satcher, RL; Siegel, HJ; Mehren, MV; Bergman, MA; Sundar, H
MLA Citation
Biermann, JS, Adkins, DR, Agulnik, M, Benjamin, RS, Brigman, B, Butrynski, JE, Cheong, D, Chow, W, Curry, WT, Frassica, DA, Frassica, FJ, Hande, KR, Hornicek, FJ, Jones, RL, Mayerson, J, McGarry, SV, McGrath, B, Morris, CD, O'donnell, RJ, Randall, RL, Santana, VM, Satcher, RL, Siegel, HJ, Mehren, MV, Bergman, MA, and Sundar, H. "Bone Cancer: Clinical practice guidelines in oncology." JNCCN Journal of the National Comprehensive Cancer Network 11.6 (2013): 688-723.
PMID
23744868
Source
scival
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
11
Issue
6
Publish Date
2013
Start Page
688
End Page
723

The vascularized fibular graft in the pediatric upper extremity: a durable, biological solution to large oncologic defects.

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.

Authors
Zelenski, N; Brigman, BE; Levin, LS; Erdmann, D; Eward, WC
MLA Citation
Zelenski, N, Brigman, BE, Levin, LS, Erdmann, D, and Eward, WC. "The vascularized fibular graft in the pediatric upper extremity: a durable, biological solution to large oncologic defects." Sarcoma 2013 (2013): 321201-.
PMID
24222724
Source
pubmed
Published In
Sarcoma
Volume
2013
Publish Date
2013
Start Page
321201
DOI
10.1155/2013/321201

Intraoperative detection and removal of microscopic residual sarcoma using wide-field imaging.

The goal of limb-sparing surgery for a soft tissue sarcoma of the extremity is to remove all malignant cells while preserving limb function. After initial surgery, microscopic residual disease in the tumor bed will cause a local recurrence in approximately 33% of patients with sarcoma. To help identify these patients, the authors developed an in vivo imaging system to investigate the suitability of molecular imaging for intraoperative visualization.A primary mouse model of soft tissue sarcoma and a wide field-of-view imaging device were used to investigate a series of exogenously administered, near-infrared (NIR) fluorescent probes activated by cathepsin proteases for real-time intraoperative imaging.The authors demonstrated that exogenously administered cathepsin-activated probes can be used for image-guided surgery to identify microscopic residual NIR fluorescence in the tumor beds of mice. The presence of residual NIR fluorescence was correlated with microscopic residual sarcoma and local recurrence. The removal of residual NIR fluorescence improved local control.The authors concluded that their technique has the potential to be used for intraoperative image-guided surgery to identify microscopic residual disease in patients with cancer.

Authors
Mito, JK; Ferrer, JM; Brigman, BE; Lee, C-L; Dodd, RD; Eward, WC; Marshall, LF; Cuneo, KC; Carter, JE; Ramasunder, S; Kim, Y; Lee, WD; Griffith, LG; Bawendi, MG; Kirsch, DG
MLA Citation
Mito, JK, Ferrer, JM, Brigman, BE, Lee, C-L, Dodd, RD, Eward, WC, Marshall, LF, Cuneo, KC, Carter, JE, Ramasunder, S, Kim, Y, Lee, WD, Griffith, LG, Bawendi, MG, and Kirsch, DG. "Intraoperative detection and removal of microscopic residual sarcoma using wide-field imaging." Cancer 118.21 (November 2012): 5320-5330.
PMID
22437667
Source
epmc
Published In
Cancer
Volume
118
Issue
21
Publish Date
2012
Start Page
5320
End Page
5330
DOI
10.1002/cncr.27458

Surgical treatment and prognosis in patients with high-grade soft tissue malignant fibrous histiocytoma of the extremities.

BACKGROUND: Malignant fibrous histiocytoma (MFH) of soft tissue is one of the most common sarcoma in adulthood. However, only a few series have separately studied the clinical behavior and prognosis of this malignancy. METHODS: We retrospectively reviewed 61 patients treated for extremity soft tissue high-grade MFH. Four patients had a history of another malignancy and were excluded from analysis. In 12 referred patients with incomplete excision, re-excision of the tumor bed was offered. Clinical and treatment variables were analyzed for their impact on treatment complications, local recurrence (LR), metastatic disease (MD) and overall survival (OS). RESULTS: Four patients underwent primary amputation. Twenty-three patients necessitated a primary reconstructive procedure for wound closure. Wound healing complication (WHC) developed in 28.3 % of the limb sparing group of patients. LR developed in 11 patients (19.3 %), while 6 of them had second LR. Eighteen patients (31.5 %) developed MD, involving lung at least. Patients who developed MD <12  vs >12 months, died within 19.3 vs 8 months mean time (p < 0.05). Overall survivorship was 66.7 % at 5 years. No statistically significant variables were identified for LR, while multivariate analysis for MD revealed tumor size >5 cm as the only statistically significant variable. For OS, development of MD and age >70 years emerged as independent prognostic factors. CONCLUSIONS: The overall prognosis is poor. LR, although can be managed with tumor re-excision, has high second recurrence rate. Increased tumor size is associated with shorter metastasis-free interval which significantly decreases survival.

Authors
Vasileios, KA; Eward, WC; Brigman, BE
MLA Citation
Vasileios, KA, Eward, WC, and Brigman, BE. "Surgical treatment and prognosis in patients with high-grade soft tissue malignant fibrous histiocytoma of the extremities." Arch Orthop Trauma Surg 132.7 (July 2012): 955-961.
PMID
22487849
Source
pubmed
Published In
Archives of Orthopaedic and Trauma Surgery
Volume
132
Issue
7
Publish Date
2012
Start Page
955
End Page
961
DOI
10.1007/s00402-012-1510-y

Leiomyosarcoma of the somatic soft tissues.

Leiomyosarcomas of the somatic soft tissues are tumors of smooth muscle origin that occur in the extremities. These lesions are commonly high-grade tumors that carry a poor prognosis. Recommended treatment often includes wide excision and chemotherapy or radiation therapy. Sixty-five patients were followed for a mean of 4.1 years. The mean maximum tumor diameter was 7 cm, and approximately 70% of all patients had tumors deep to fascia. Including all stages of disease, the overall 1-, 2-, and 5-year survival rates were 91%, 87%, and 68%, respectively. Mitotic rate and tumor depth were significant predictors of development of recurrent disease and metastatic disease. Tumor size was another predictor of recurrent disease. The mitotic rate and AJCC stage were also important predictors of overall survival. Patients with deep lesions, histologic grade 3 disease/higher mitotic rates, and advanced stage of disease had a poorer prognosis and thus were more likely to undergo adjuvant chemotherapy. Future clinical studies may help determine if knowledge of these predictors can help guide treatment and improve clinical outcomes.

Authors
Radkowski, CA; Dodd, LG; Johnson, JL; Harrelson, JM; Brigman, BE
MLA Citation
Radkowski, CA, Dodd, LG, Johnson, JL, Harrelson, JM, and Brigman, BE. "Leiomyosarcoma of the somatic soft tissues." J Surg Orthop Adv 21.2 (2012): 96-101.
PMID
22995359
Source
pubmed
Published In
Journal of surgical orthopaedic advances
Volume
21
Issue
2
Publish Date
2012
Start Page
96
End Page
101

[Femur reconstruction using combined autologous fibula transfer and humeral allograft].

Wide resection far into the femoral metaphysis may be required to treat malignant bone tumors in the pediatric and adolescent patient population. Biological reconstruction using a free, vascularized fibular graft is a well-established surgical technique. A short remaining femoral medullary canal and a relatively small fibula diameter can make fixation of the vascularized bone transfer difficult. Stable fixation and short fusion times, however, can be achieved with the use of an additional humeral allograft and plate osteosynthesis.

Authors
Kokosis, G; Stolberg-Stolberg, J; Eward, WC; Richard, MJ; Hollenbeck, ST; Levinson, H; Brigman, BE; Erdmann, D
MLA Citation
Kokosis, G, Stolberg-Stolberg, J, Eward, WC, Richard, MJ, Hollenbeck, ST, Levinson, H, Brigman, BE, and Erdmann, D. "[Femur reconstruction using combined autologous fibula transfer and humeral allograft]." Chirurg 82.12 (December 2011): 1120-1123.
PMID
21901467
Source
pubmed
Published In
Der Chirurg
Volume
82
Issue
12
Publish Date
2011
Start Page
1120
End Page
1123
DOI
10.1007/s00104-011-2165-x

Role of mitogen-activated protein kinase in osteoblast differentiation.

Local control of osteoblast differentiation and bone formation is not well understood. We have previously seen biphasic effects on cell differentiation in response to the short- and long-term exposure to IL-1β in rat calvarial osteoblasts. To characterize the signaling pathway mechanisms regulating IL-1β biphasic effects, we examined the contribution of mitogen-activated protein kinase (MAPK) family. Cells were pretreated with specific inhibitors to extracellular signal-regulated kinase (ERK, PD98059), p38 (SB203580), and c-JUN N-terminal kinase (JNK, SP600125), then co-cultured with IL-1β for 2, 4, and 6 days. Cell differentiation was determined by measuring bone nodules after 10 days of culture. These inhibitors did not alter biphasic effects of IL-1β on cell differentiation. However, PD98059 and U2016, another inhibitor of ERK activation robustly increased osteoblast differentiation compared to vehicle-treated control in a time- and dose-dependent manner. PD98059 appears to stimulate alkaline phosphatase (ALP) activity to promote cell differentiation, where IL-1β appears to suppress it. Interestingly, continuous ERK inhibition with PD98059, after 2 and 4 days of IL-1β treatment, enhanced the IL-1β anabolic effect by increasing bone nodules formed. These observations provide a potential mechanism involving ERK pathway in osteoblasts differentiation and suggest that MAPK family may not directly regulate IL-1β biphasic effects.

Authors
Lin, F-H; Chang, JB; Brigman, BE
MLA Citation
Lin, F-H, Chang, JB, and Brigman, BE. "Role of mitogen-activated protein kinase in osteoblast differentiation." J Orthop Res 29.2 (February 2011): 204-210.
PMID
20806320
Source
pubmed
Published In
Journal of Orthopaedic Research
Volume
29
Issue
2
Publish Date
2011
Start Page
204
End Page
210
DOI
10.1002/jor.21222

Dissecting molecular mechanisms of metastasis in a primary mouse model of soft tissue sarcoma

Authors
Mito, JK; Dodd, RD; Brigman, BE; Li, Z; Eward, WC; Mukherjee, S; Kirsch, D
MLA Citation
Mito, JK, Dodd, RD, Brigman, BE, Li, Z, Eward, WC, Mukherjee, S, and Kirsch, D. "Dissecting molecular mechanisms of metastasis in a primary mouse model of soft tissue sarcoma." CLINICAL & EXPERIMENTAL METASTASIS 28.2 (February 2011): 166-167.
Source
wos-lite
Published In
Clinical & Experimental Metastasis
Volume
28
Issue
2
Publish Date
2011
Start Page
166
End Page
167

Effects of Radiation Therapy on the Detection of Microscopic Residual Cancer in the Surgical Bed using a Protease-activated Fluorescent Probe in a Primary Soft Tissue Sarcoma Model

Authors
Cuneo, KC; Mito, JK; Brigman, BE; Ferrer, JM; Lee, C; Eward, WC; Carter, JE; Kirsch, DG
MLA Citation
Cuneo, KC, Mito, JK, Brigman, BE, Ferrer, JM, Lee, C, Eward, WC, Carter, JE, and Kirsch, DG. "Effects of Radiation Therapy on the Detection of Microscopic Residual Cancer in the Surgical Bed using a Protease-activated Fluorescent Probe in a Primary Soft Tissue Sarcoma Model." INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS 81.2 (2011): S729-S730.
Source
wos-lite
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
81
Issue
2
Publish Date
2011
Start Page
S729
End Page
S730

Case report: Neuropathic arthropathy of the hip as a sequela of undiagnosed tertiary syphilis.

BACKGROUND: Neuropathic arthropathy is characterized by rapidly progressive bone destruction in the setting of impaired nociceptive and proprioceptive innervation to the involved joint. It is seen most commonly in the foot and ankle, secondary to peripheral neuropathy in patients with diabetes mellitus. Other less common sites of involvement may include the knee, hip, shoulder, and spine, depending on the underlying etiology. Neuropathic arthropathy can be associated with tabes dorsalis, a unique manifestation of late, tertiary neurosyphilis that may arise in individuals with untreated syphilis many years after initial infection, and usually involves the knee, or less commonly, the hip. CASE REPORT: We report the case of a 73-year-old man with neuropathic arthropathy of the hip and tabes dorsalis attributable to previously undiagnosed tertiary syphilis. There was considerable delay in the diagnosis and unnecessary diagnostic testing owing to failure to consider syphilis as the cause. LITERATURE REVIEW: With the advent of effective antimicrobial therapy and public health campaigns, the relationship between untreated syphilis and neuropathic arthropathy has been primarily a historic point of interest. However, current epidemiologic research suggests a resurgence of syphilis in the United States, with an increased incidence of patients presenting with manifestations of tertiary syphilis from unidentified and untreated primary infections. Treatment options for neuropathic arthropathy of the hip are limited. Arthrodesis has had poor success and treatment with THA has had high complication rates. CONCLUSIONS: Syphilis is not merely a historic cause of neuropathic arthropathy. Neurosyphilis and tabes dorsalis should be considered in the differential diagnosis for patients presenting with rapid joint destruction consistent with Charcot arthropathy and no other apparent cause.

Authors
Viens, NA; Watters, TS; Vinson, EN; Brigman, BE
MLA Citation
Viens, NA, Watters, TS, Vinson, EN, and Brigman, BE. "Case report: Neuropathic arthropathy of the hip as a sequela of undiagnosed tertiary syphilis." Clin Orthop Relat Res 468.11 (November 2010): 3126-3131. (Review)
PMID
20151233
Source
pubmed
Published In
Clinical Orthopaedics and Related Research ®
Volume
468
Issue
11
Publish Date
2010
Start Page
3126
End Page
3131
DOI
10.1007/s11999-010-1257-0

Extremity soft tissue sarcomas presented as hematomas.

INTRODUCTION: Soft tissue sarcoma (STS) with extensive intra-tumoral hemorrhage is an infrequently described entity, usually misdiagnosed as intra-muscular hematoma. The outcomes in this group of patients have not been previously described. MATERIALS AND METHODS: We retrospectively identified 15 patients, with initial clinical or imaging diagnosis of hematoma, or hematoma versus hemorrhagic sarcoma, although final diagnosis of high-grade STS was established in all cases. RESULTS: The most common location was the thigh. Three patients had a bleeding predisposition. Ten patients were referred for further evaluation with the initial diagnosis of muscle strain/hematoma, hematoma versus abscess in one, whereas four were referred for soft tissue mass evaluation. Final diagnosis was made by one biopsy in only 53% of patients. Mean time to diagnosis for patients with two biopsies was 7 months from initial presentation. Histologic diagnosis was malignant fibrous histiocytoma in ten patients. Surgical treatment included tumor resection in eleven and amputation in three patients. One patient had lung metastatic disease at presentation and eight developed lung metastases within a median time of 7 months. CONCLUSION: We suggest that an STS masquerading as hematoma should be suspected when the mechanism and the energy of the trauma do not justify the clinically detected severity of the injury, or the lesion does not follow the expected clinical course of resolution after initial conservative management. Bleeding predisposition does not exclude malignancy. The evacuation of hematomas should include pathologic examination of tissue. Prognosis is dismal due to early metastatic disease.

Authors
Kontogeorgakos, VA; Martinez, S; Dodd, L; Brigman, BE
MLA Citation
Kontogeorgakos, VA, Martinez, S, Dodd, L, and Brigman, BE. "Extremity soft tissue sarcomas presented as hematomas." Arch Orthop Trauma Surg 130.10 (October 2010): 1209-1214.
PMID
19838719
Source
pubmed
Published In
Archives of Orthopaedic and Trauma Surgery
Volume
130
Issue
10
Publish Date
2010
Start Page
1209
End Page
1214
DOI
10.1007/s00402-009-0987-5

Biphasic effects of interleukin-1beta on osteoblast differentiation in vitro.

A rat calvarial cell model of osteoblast differentiation using the formation of bone nodules in vitro as an endpoint was used to assess the effects of IL-1beta on osteoblast differentiation. Short-term treatment (2 days) with IL-1beta early in culture resulted in increased nodule number and size as well as calcium content in contrast to long-term treatment (6 days) in cultures assessed at 10-12 days. This increase in bone formation was blocked by IL-1 receptor antagonists. Short-term treatment increased COX-2, prostaglandin (PGE(2)), and iNOS production. Exogenous PGE(2) with IL-1beta enhanced this effect. COX-2 inhibitors, indomethacin and N-39, blocked 50% of nodule formation. NO donor did not modify effects of IL-1beta, but iNOS inhibitor (1400W) partially blocked the effects. However, PGE(2) and NO donors could not rescue the decreased nodule number resulting from long-term IL-1beta treatment. The results of this study suggest a biphasic effect of IL-1beta on bone nodule formation activated by IL-1beta binding with IL-1 receptors, and the anabolic effect of early short-term treatment with IL-1beta is likely mediated by PGE without ruling out nitric oxide.

Authors
Lin, F-H; Chang, JB; McGuire, MH; Yee, JA; Brigman, BE
MLA Citation
Lin, F-H, Chang, JB, McGuire, MH, Yee, JA, and Brigman, BE. "Biphasic effects of interleukin-1beta on osteoblast differentiation in vitro." J Orthop Res 28.7 (July 2010): 958-964.
PMID
20108347
Source
pubmed
Published In
Journal of Orthopaedic Research
Volume
28
Issue
7
Publish Date
2010
Start Page
958
End Page
964
DOI
10.1002/jor.21099

Free vascularized fibular graft reconstruction of large skeletal defects after tumor resection.

UNLABELLED: Skeletal reconstruction of large tumor resection defects is challenging. Free vascularized fibular transfer offers the potential for rapid autograft incorporation in limbs compromised by adjuvant chemotherapy or radiation. We retrospectively reviewed 30 patients treated with free vascularized fibular graft reconstruction of large skeletal defects after tumor resections (mean defect length, 14.8 cm). The minimum followup was 2 years (mean, 4.9 years; range, 2-15 years). One patient died with liver and lung metastases at 3 years postoperatively. Loss of limb occurred in one patient. Five patients either had metastatic disease (one patient) or had metastatic disease (four patients) develop after treatment, with a mean time to metastasis of 18 months. The overall complication rate was 16 of 30 (53%), with a reoperation rate of 12 of 30 (40%). Union was attained in all 30 grafts. Primary union was attained in 23 (77%) at a mean of 6 months. Secondary union was achieved in seven (23%) after revision fixation and bone grafting; the mean subsequent time to union was 9.2 months, with an index of 1.33 additional operations per patient. Graft fracture (20%) and infection (10%) were other common complications. Despite a high complication rate, free vascularized fibular graft reconstruction offers a reliable treatment of large skeletal defects after tumor resection without increased risk of limb loss, local recurrence, or tumor metastasis. LEVEL OF EVIDENCE: Level IV, case series. See Guidelines for Authors for a complete description of levels of evidence.

Authors
Eward, WC; Kontogeorgakos, V; Levin, LS; Brigman, BE
MLA Citation
Eward, WC, Kontogeorgakos, V, Levin, LS, and Brigman, BE. "Free vascularized fibular graft reconstruction of large skeletal defects after tumor resection." Clin Orthop Relat Res 468.2 (February 2010): 590-598.
PMID
19701672
Source
pubmed
Published In
Clinical Orthopaedics and Related Research ®
Volume
468
Issue
2
Publish Date
2010
Start Page
590
End Page
598
DOI
10.1007/s11999-009-1053-x

Cryptococcal abscess imitating a soft-tissue sarcoma in an immunocompetent host: A case report

Authors
Gaskill, T; Payne, D; Brigman, B
MLA Citation
Gaskill, T, Payne, D, and Brigman, B. "Cryptococcal abscess imitating a soft-tissue sarcoma in an immunocompetent host: A case report." Journal of Bone and Joint Surgery - Series A 92.9 (2010): 1890-1893.
PMID
20686064
Source
scival
Published In
The Journal of Bone and Joint Surgery
Volume
92
Issue
9
Publish Date
2010
Start Page
1890
End Page
1893
DOI
10.2106/JBJS.I.01091

Bone cancer

Primary bone cancers are rare neoplasms, with osteosarcoma, chondrosarcoma, and Ewing's sarcoma the 3 most common forms. Chondrosarcoma is usually found in middle-aged and older adults. Wide excision is the preferred treatment for resectable low- and high-grade chondrosarcomas. Intralesional excision with or without adjuvant therapy is an alternative option for low-grade lesions. In small series of reports, the addition of chemotherapy improved outcomes in patients with mesenchymal chondrosarcomas. However, the role of chemotherapy in the treatment of chondrosarcomas is not yet defined. Ewing's sarcoma is characterized by a chromosomal translocation t(11;22), resulting in the fusion of EWS gene with various members of the ETS family of genes, and develops mainly in children and young adults. Multiagent chemotherapy is the primary treatment for patients with Ewing's sarcoma. Patients who experience response to primary treatment are treated with local control therapy (surgery or radiation) followed by adjuvant chemotherapy. Progressive disease is best managed with RT with or without surgery followed by chemotherapy or best supportive care. Osteosarcoma occurs mainly in children and young adults. Wide excision is the primary treatment for patients with low-grade osteosarcomas, whereas preoperative chemotherapy is preferred before wide excision for high-grade osteosarcoma and periosteal lesions. After wide excision (for resectable lesions), postoperative chemotherapy is recommended for patients with low-grade or periosteal sarcomas with pathologic findings of high-grade disease and those with high-grade sarcoma. RT followed by adjuvant chemotherapy is recommended if the sarcoma remains unresectable after preoperative chemotherapy. Patients with relapsed or refractory disease should be treated with second-line therapy. Participation in a clinical trial should be strongly encouraged for patients experiencing progressive disease after second-line therapy. The development of multiagent chemotherapy regimens for neoadjuvant and adjuvant treatment has considerably improved the prognosis for patients with osteosarcoma and Ewing's sarcoma. A small subset of patients diagnosed with metastatic disease at presentation can be cured with the proper treatment. Consistent with the NCCN philosophy, the panel encourages patients to participate in well-designed clinical trials to enable further advances. © Journal of the National Comprehensive Cancer Network.

Authors
Biermann, JS; Adkins, DR; Benjamin, RS; Brigman, B; Chow, W; III, EUC; Frassica, DA; Frassica, FJ; George, S; Hande, KR; Hornicek, FJ; Letson, GD; Mayerson, J; McGarry, SV; McGrath, B; Morris, CD; O'Donnell, RJ; Randall, RL; Santana, VM; Satcher, RL; Siegel, HJ; Somaiah, N; Yasko, AW
MLA Citation
Biermann, JS, Adkins, DR, Benjamin, RS, Brigman, B, Chow, W, III, EUC, Frassica, DA, Frassica, FJ, George, S, Hande, KR, Hornicek, FJ, Letson, GD, Mayerson, J, McGarry, SV, McGrath, B, Morris, CD, O'Donnell, RJ, Randall, RL, Santana, VM, Satcher, RL, Siegel, HJ, Somaiah, N, and Yasko, AW. "Bone cancer." JNCCN Journal of the National Comprehensive Cancer Network 8.6 (2010): 688-712.
PMID
20581300
Source
scival
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
8
Issue
6
Publish Date
2010
Start Page
688
End Page
712

Cross species genomic analysis identifies a mouse model as undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma.

Undifferentiated pleomorphic sarcoma/Malignant Fibrous Histiocytoma (MFH) is one of the most common subtypes of human soft tissue sarcoma. Using cross species genomic analysis, we define a geneset from the LSL-Kras(G12D); Trp53(Flox/Flox) mouse model of soft tissue sarcoma that is highly enriched in human MFH. With this mouse geneset as a filter, we identify expression of the RAS target FOXM1 in human MFH. Expression of Foxm1 is elevated in mouse sarcomas that metastasize to the lung and tissue microarray analysis of human MFH correlates overexpression of FOXM1 with metastasis. These results suggest that genomic alterations present in human MFH are conserved in the LSL-Kras(G12D); p53(Flox/Flox) mouse model of soft tissue sarcoma and demonstrate the utility of this pre-clinical model.

Authors
Mito, JK; Riedel, RF; Dodd, L; Lahat, G; Lazar, AJ; Dodd, RD; Stangenberg, L; Eward, WC; Hornicek, FJ; Yoon, SS; Brigman, BE; Jacks, T; Lev, D; Mukherjee, S; Kirsch, DG
MLA Citation
Mito, JK, Riedel, RF, Dodd, L, Lahat, G, Lazar, AJ, Dodd, RD, Stangenberg, L, Eward, WC, Hornicek, FJ, Yoon, SS, Brigman, BE, Jacks, T, Lev, D, Mukherjee, S, and Kirsch, DG. "Cross species genomic analysis identifies a mouse model as undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma. (Published online)" PLoS One 4.11 (November 30, 2009): e8075-.
PMID
19956606
Source
pubmed
Published In
PloS one
Volume
4
Issue
11
Publish Date
2009
Start Page
e8075
DOI
10.1371/journal.pone.0008075

The clinical management of chondrosarcoma.

OPINION STATEMENT: Chondrosarcomas (CHS) represent a heterogeneous group of disorders ranging from indolent, low-grade tumors to aggressive, high-grade forms. Surgical resection represents the primary and preferred treatment modality for individuals with localized disease. Radiation therapy is appropriate for the treatment of positive surgical margins or palliation of disease-related symptoms. The treatment of advanced, metastatic disease is particularly challenging given the recognition that conventional chemotherapy has proven to be largely ineffective. Systemic chemotherapy may be considered in variant forms such as mesenchymal or dedifferentiated chondrosarcomas but high-quality data supporting its use is limited. There is universal agreement, however, that novel treatment strategies are desperately needed. This review will highlight the need for a coordinated multidisciplinary approach to optimize the management and care of patients.

Authors
Riedel, RF; Larrier, N; Dodd, L; Kirsch, D; Martinez, S; Brigman, BE
MLA Citation
Riedel, RF, Larrier, N, Dodd, L, Kirsch, D, Martinez, S, and Brigman, BE. "The clinical management of chondrosarcoma." Curr Treat Options Oncol 10.1-2 (April 2009): 94-106. (Review)
PMID
19238552
Source
pubmed
Published In
Current Treatment Options in Oncology
Volume
10
Issue
1-2
Publish Date
2009
Start Page
94
End Page
106
DOI
10.1007/s11864-009-0088-2

Cortical desmoid and the four clinical scenarios

We reviewed four patients diagnosed with a cortical desmoid lesion at the distal posterior medial femur. Each case reflects a clinical scenario that can be present. Cortical desmoid is a benign, self-limited entity which occasionally can exhibit aggressive radiologic features. Here, we present the specific imaging features in association with patients history and clinical findings facilitating establishment of correct diagnosis. Exact diagnosis is important in order to avoid unnecessary biopsy and complicated therapeutic strategies. © Springer-Verlag 2008.

Authors
Kontogeorgakos, VA; Xenakis, T; Papachristou, D; Korompilias, A; Kanellopoulos, A; Beris, A; Brigman, B
MLA Citation
Kontogeorgakos, VA, Xenakis, T, Papachristou, D, Korompilias, A, Kanellopoulos, A, Beris, A, and Brigman, B. "Cortical desmoid and the four clinical scenarios." Archives of Orthopaedic and Trauma Surgery 129.6 (2009): 779-785.
PMID
18612646
Source
scival
Published In
Archives of Orthopaedic and Trauma Surgery
Volume
129
Issue
6
Publish Date
2009
Start Page
779
End Page
785
DOI
10.1007/s00402-008-0687-6

Acral myxoinflammatory fibroblastic sarcomas: MRI findings in four cases.

OBJECTIVE: Acral myxoinflammatory fibroblastic sarcoma is a rare, recently described, low-grade sarcoma that involves mainly the distal extremities. The purpose of this study is to report the MRI findings in four cases of acral myxoinflammatory fibroblastic sarcoma. CONCLUSION: Acral myxoinflammatory fibroblastic sarcomas may present with various MRI patterns that probably reflect their variable histologic composition. Differential diagnosis with other benign conditions, especially with ganglion cysts and giant cell tumors of the tendon sheath, may be difficult. We report tumoral invasion of the bone in one case, which to our knowledge has not been previously described.

Authors
Narváez, JA; Martinez, S; Dodd, LG; Brigman, BE
MLA Citation
Narváez, JA, Martinez, S, Dodd, LG, and Brigman, BE. "Acral myxoinflammatory fibroblastic sarcomas: MRI findings in four cases." AJR Am J Roentgenol 188.5 (May 2007): 1302-1305.
PMID
17449774
Source
pubmed
Published In
AJR. American journal of roentgenology
Volume
188
Issue
5
Publish Date
2007
Start Page
1302
End Page
1305
DOI
10.2214/AJR.05.0141

Bone cancer: Clinical Practice Guidelines in Oncology™

Primary bone cancers are extremely rare neoplasms, accounting for less than 0.2% of all cancers. Primary bone cancers show wide clinical heterogeneity and, perhaps most importantly, are often curable. With current multimodality treatment, including multi-agent chemotherapy, approximately three quarters of all patients diagnosed with osteosarcoma are cured. Updates for 2007 include changes in recommendations for treating chondrosarcoma, Ewing's sarcoma, and osteosarcoma. © Journal of the National Comprehensive Cancer Network 2007.

Authors
Biermann, JS; Adkins, D; Benjamin, R; Brigman, B; Chow, W; III, EUC; Frassica, D; Frassica, FJ; George, S; Healey, JH; Jr, RH; Letson, GD; Mayerson, J; McGarry, SV; O'Donnell, RJ; Patt, J; Randall, RL; Santana, V; Satcher, RL; Schmidt, RG; Siegel, HJ; Wong, MK; Yasko, AW
MLA Citation
Biermann, JS, Adkins, D, Benjamin, R, Brigman, B, Chow, W, III, EUC, Frassica, D, Frassica, FJ, George, S, Healey, JH, Jr, RH, Letson, GD, Mayerson, J, McGarry, SV, O'Donnell, RJ, Patt, J, Randall, RL, Santana, V, Satcher, RL, Schmidt, RG, Siegel, HJ, Wong, MK, and Yasko, AW. "Bone cancer: Clinical Practice Guidelines in Oncology™." JNCCN Journal of the National Comprehensive Cancer Network 5.4 (2007): 420-437.
PMID
17442233
Source
scival
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
5
Issue
4
Publish Date
2007
Start Page
420
End Page
437

Case reports: acral myxoinflammatory fibroblastic sarcoma: a report of five cases and literature review.

During the past 2 years, we treated five patients with acral myxoinflammatory fibroblastic sarcoma at our institution. Four patients presented with a firm, painless mass in the hand that appeared over several months. One patient discovered a painless mass in his shoulder region. The five patients initially were diagnosed as having benign conditions and treated with intralesional or marginal excision by referring physicians, only to have the lesion reappear as sarcoma. Each patient was treated with wide resection of the tumor bed. Acral myxoinflammatory fibroblastic sarcoma is a rare, but increasingly recognized sarcoma of the distal extremities, which often is confused with benign lesions. Surgeons should be familiar with this tumor's clinical, radiographic, and histologic appearances as it has a high rate of recurrence and can metastasize.

Authors
Lang, JE; Dodd, L; Martinez, S; Brigman, BE
MLA Citation
Lang, JE, Dodd, L, Martinez, S, and Brigman, BE. "Case reports: acral myxoinflammatory fibroblastic sarcoma: a report of five cases and literature review." Clin Orthop Relat Res 445 (April 2006): 254-260. (Review)
PMID
16446594
Source
pubmed
Published In
Clinical Orthopaedics and Related Research ®
Volume
445
Publish Date
2006
Start Page
254
End Page
260
DOI
10.1097/01.blo.0000201158.67443.a2

Upper extremity compartmental anatomy: clinical relevance to radiologists.

Malignant tumors of the upper extremity are uncommon, and their care should be referred to specialized facilities with experience treating these lesions. The Musculoskeletal Tumor Society (MSTS) staging system is used by the surgeon to determine appropriate surgical management, assess prognosis, and communicate with other healthcare providers. Magnetic resonance imaging (MRI) is employed pre-operatively to identify a lesion's compartment of origin, determine extent of spread, and plan biopsy and resection approaches. Involvement of neurovascular structures may result in devastating loss of upper extremity function, requiring amputation. Violation of high-resistance compartmental barriers necessitates more extensive surgical resection. Biopsy may be performed by the radiologist using imaging guidance. Knowledge of compartmental anatomy allows the radiologist or surgeon to use an easily excisable biopsy approach and prevent iatrogenic spread to unaffected compartments. Case examples are presented to illustrate the importance of compartmental anatomy in the management of benign and malignant upper extremity tumors.

Authors
Toomayan, GA; Robertson, F; Major, NM; Brigman, BE
MLA Citation
Toomayan, GA, Robertson, F, Major, NM, and Brigman, BE. "Upper extremity compartmental anatomy: clinical relevance to radiologists." Skeletal Radiol 35.4 (April 2006): 195-201. (Review)
PMID
16489465
Source
pubmed
Published In
Skeletal Radiology
Volume
35
Issue
4
Publish Date
2006
Start Page
195
End Page
201
DOI
10.1007/s00256-005-0063-3

Stacking of a dermal regeneration template for reconstruction of a soft-tissue defect after tumor excision from the palm of the hand: a case report.

Excision of tumors from the hand often leaves tissue defects with exposed tendons or neurovascular structures that require coverage. Various types of free and pedicled grafts have been described for use in these situations. We present a patient who had a tumor excision in the hand followed by wound coverage with a stacked dermal regeneration template. A 50-year-old man presented with a mass over the palm of the hand. He had an incisional biopsy procedure, the results of which suggested malignancy. He then had wide excision with planned temporary skin coverage with a dermal regeneration template. The dermal template incorporated nicely. With adequate skin coverage the palmar defect still was substantial in terms of depth. This was raised with layering or stacking of the template followed by a split-thickness skin graft. Excellent wound healing and coverage of the defect ultimately were achieved. Additionally the patient went on to obtain full range of motion. Stacking of a dermal regeneration template coupled with split-thickness skin grafting was used to fill a soft-tissue defect over the median and nerve and flexor tendons after wide tumor excision.

Authors
Carothers, JT; Brigman, BE; Lawson, RD; Rizzo, M
MLA Citation
Carothers, JT, Brigman, BE, Lawson, RD, and Rizzo, M. "Stacking of a dermal regeneration template for reconstruction of a soft-tissue defect after tumor excision from the palm of the hand: a case report." J Hand Surg Am 30.6 (November 2005): 1322-1326.
PMID
16344197
Source
pubmed
Published In
Journal of Hand Surgery (American Volume)
Volume
30
Issue
6
Publish Date
2005
Start Page
1322
End Page
1326
DOI
10.1016/j.jhsa.2005.08.001

Bone cancer: Clinical practice guidelines

Primary bone cancers are extremely uncommon, comprise many different types with wide clinical heterogeneity, and are often curable when treated properly. There are many different kinds of primary bone cancers, and the names are principally based on histologic origin. For certain sarcomas, the cell type of origin has not yet been specifically determined. The three most common primary bone sarcomas are osteosarcoma (35%), chondrosarcoma (30%), and the Ewing's family of tumors (16%). Today, approximately three quarters of all newly diagnosed patients with osteosarcoma are cured. Of adult patients with osteosarcoma, nearly 95% can be treated successfully with limb-salvage approaches rather than amputation. Similar cure rates are associated with the Ewing's family of tumors, and in both osteosarcoma and Ewing's, cure is still achievable, even when lung metastasis occurs. © Journal of the National Comprehensive Cancer Network.

Authors
Biermann, JS; Baker, LH; Benjamin, R; Brigman, B; Chow, W; III, EUC; Frassica, D; Frassica, FJ; George, S; Healey, JH; Heck, R; Letson, GD; Mayerson, J; Neff, J; O'Donnell, RJ; Randall, RL; Santana, V; Satcher, RL; Schmidt, RG; Siegel, HJ; Wong, MK; Yasko, AW
MLA Citation
Biermann, JS, Baker, LH, Benjamin, R, Brigman, B, Chow, W, III, EUC, Frassica, D, Frassica, FJ, George, S, Healey, JH, Heck, R, Letson, GD, Mayerson, J, Neff, J, O'Donnell, RJ, Randall, RL, Santana, V, Satcher, RL, Schmidt, RG, Siegel, HJ, Wong, MK, and Yasko, AW. "Bone cancer: Clinical practice guidelines." JNCCN Journal of the National Comprehensive Cancer Network 3.2 (2005): 124-140.
PMID
19817025
Source
scival
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
3
Issue
2
Publish Date
2005
Start Page
124
End Page
140

Malignant giant cell tumor of soft parts.

Giant cell tumor of soft parts (GCTSP) is an extremely rare lesion with an unpredictable behavior. Some patients are cured with a simple surgical excision whereas others will develop metastatic disease within a relatively short interval. To date, there are no consistently reliable criteria, either clinical or histologic, to separate the benign from more aggressive lesions. We describe the clinical, histologic and radiologic features of a case with malignant behavior. The patient presented with a fungating skin and soft tissue mass and concurrent pulmonary nodules. The lesion recurred rapidly despite wide resection with negative surgical margins. Biopsy of the pulmonary lesions demonstrated metastatic disease.

Authors
Dodd, LG; Major, N; Brigman, B
MLA Citation
Dodd, LG, Major, N, and Brigman, B. "Malignant giant cell tumor of soft parts." Skeletal Radiol 33.5 (May 2004): 295-299.
PMID
14997349
Source
pubmed
Published In
Skeletal Radiology
Volume
33
Issue
5
Publish Date
2004
Start Page
295
End Page
299
DOI
10.1007/s00256-003-0744-8

Allografts about the Knee in Young Patients with High-Grade Sarcoma.

Reconstruction after resections for high-grade sarcomas about the knee in children and adolescents is a challenging problem because of the large soft tissue and skeletal defects, the effects of adjuvant therapy, and the potential for long-term use of the limb. One hundred sixteen patients, all 18 years or younger, with osteosarcoma or Ewing's sarcoma located between the middle femur and middle tibia, were treated with chemotherapy, resection, and allograft reconstruction. One hundred three patients with osteosarcoma and 13 patients with Ewing's sarcoma had 105 Stage II and 11 Stage III tumors. There were 72 osteoarticular grafts (39 femur, 33 tibia), 28 intercalary grafts (19 femur), seven allograft-prosthetic composites (all femur,) and nine allograft-arthrodeses (seven femur, two tibia). At latest followup, 49% of all of the allograft reconstructions were rated good or excellent, 14% were rated as fair, and 37% were failures. Sixteen percent had an infection develop. Twenty-seven percent of patients had a fracture, 34% had a nonunion, and 14 patients eventually required amputation. Reconstruction of large bone defects about the knee in young patients who are being treated with chemotherapy is difficult. Although complications significantly affect outcome, allografts are a viable option for reconstruction in children with high-grade sarcomas about the knee.

Authors
Brigman, BE; Hornicek, FJ; Gebhardt, MC; Mankin, HJ
MLA Citation
Brigman, BE, Hornicek, FJ, Gebhardt, MC, and Mankin, HJ. "Allografts about the Knee in Young Patients with High-Grade Sarcoma." Clin Orthop Relat Res 421 (April 2004): 232-239.
PMID
15123953
Source
pubmed
Published In
Clinical Orthopaedics and Related Research ®
Issue
421
Publish Date
2004
Start Page
232
End Page
239

Rotationplasty after failed limb-sparing tumor surgery: a report of two cases.

Rotationplasty was used in two cases of failed limb salvage in adults after tumor resection and reconstruction. Each patient had distal femoral osteosarcoma, one treated with osteoarticular allograft reconstruction, the other with a custom endoprosthetic reconstruction. Both patients had failure attributable to infection, and after multiple surgeries, elected to have rotationplasty. Both had complications associated with the rotationplasty but went on to have functional limbs with Musculoskeletal Tumor Society functional scores of 67% and 87%. One patient died of metastatic disease 29 months after rotationplasty, the other had no problems 50 months after rotationplasty. Although rotationplasty offers a functional improvement over transfemoral amputation in the salvage of failed tumor reconstructions, only 10 such cases have been reported in adults. Rotationplasty should be considered in selected patients for whom an amputation is being considered after failed limb salvage surgery.

Authors
Brigman, BE; Kumagai, SG; McGuire, MH
MLA Citation
Brigman, BE, Kumagai, SG, and McGuire, MH. "Rotationplasty after failed limb-sparing tumor surgery: a report of two cases." Clin Orthop Relat Res 415 (October 2003): 254-260.
PMID
14612654
Source
pubmed
Published In
Clinical Orthopaedics and Related Research ®
Issue
415
Publish Date
2003
Start Page
254
End Page
260
DOI
10.1097/01.blo.0000093887.12372.3d

Jaffe-Campanacci syndrome. A case report and review of the literature.

Authors
Hau, MA; Fox, EJ; Cates, JM; Brigman, BE; Mankin, HJ
MLA Citation
Hau, MA, Fox, EJ, Cates, JM, Brigman, BE, and Mankin, HJ. "Jaffe-Campanacci syndrome. A case report and review of the literature." The Journal of bone and joint surgery. American volume 84-A.4 (April 2002): 634-638. (Academic Article)
PMID
11940628
Source
manual
Published In
The Journal of Bone and Joint Surgery
Volume
84-A
Issue
4
Publish Date
2002
Start Page
634
End Page
638

Insulin-like growth factor-I is expressed by avian flexor tendon cells

Cells in normal tendon are in a resting G0 state, performing maintenance functions. However, traumatic injury introduces growth factors such as platelet-derived growth factor and insulin-like growth factor from blood as well as activates endogenous growth factors. These factors stimulate migration and proliferation of tendon cells at the wound area. Tendon cells require growth-promoting factors to transit the cell cycle. To evaluate the contribution of endogenous growth factors in tendon, extracts of the epitenon and internal compartment of avian flexor tendon as well as medium of cultured cells from the epitenon (tendon surface cells) and internal tendon (tendon internal fibroblasts) were collected to assess their ability to stimulate DNA synthesis. Acid-ethanol extracts of tissues and medium were chromatographed on a P-30 molecular sieve column and assayed for mitogenic activity by quantitating [3H]thymidine incorporation into tendon cell DNA. The extract from the internal tendon compartment was more stimulatory for DNA synthesis than that from the epitenon, particularly when tested on tendon internal fibroblasts. However, conditioned medium fractions from surface epitenon cells stimulated DNA synthesis to a high degree on both tendon surface cells and tendon internal fibroblasts. Conditioned medium from tendon internal fibroblasts was also stimulatory. An anti-insulin-like growth factor-I antibody ablated most of the mitogenic activity present in both tissues and conditioned medium. The levels of acid-extractable insulin-like growth factor-I in tendon were determined by competitive radio-immunoassay as 1.48 ± 0.05 ng/g tissue for the epitenon and 3.83 ± 0.03 ng/g tissue for the internal compartment. Results of Western immunoblots of conditioned medium revealed insulin-like growth factor-I at the 7.5 kDa position. Cultured tendon surface cells and tendon internal fibroblasts as well as cells in intact flexor tendon expressed insulin-like growth factor-I mRNA detected by reverse transcriptase-polymerase chain reaction. In situ hybridization histochemistry positively identified insulin-like growth factor-I mRNA in tendons from 52-day-old chickens. Platelet-derived growth factor was not detected at the protein or message levels. Furthermore, tendon surface cells and tendon internal fibroblasts both expressed receptors for insulin-like growth factor-I detected by flow cytometry. These data suggest that tendon cells express insulin-like growth factor-I mRNA and synthesize insulin-like growth factor-I in both the epitenon and the internal compartment of tendon, which is present in an inactive form, most likely bound to insulin-like growth factor-binding proteins.

Authors
Tsuzaki, M; Brigman, BE; Yamamoto, J; Lawrence, WT; Simmons, JG; Mohapatra, NK; Lund, PK; Wyk, JV; Hannafin, JA; Bhargava, MM; Banes, AJ
MLA Citation
Tsuzaki, M, Brigman, BE, Yamamoto, J, Lawrence, WT, Simmons, JG, Mohapatra, NK, Lund, PK, Wyk, JV, Hannafin, JA, Bhargava, MM, and Banes, AJ. "Insulin-like growth factor-I is expressed by avian flexor tendon cells." Journal of Orthopaedic Research 18.4 (2000): 546-556.
PMID
11052490
Source
scival
Published In
Journal of Orthopaedic Research
Volume
18
Issue
4
Publish Date
2000
Start Page
546
End Page
556

PDGF-BB, IGF-I and mechanical load stimulate DNA synthesis in avian tendon fibroblasts in vitro

Resident cells in the surface epitenon and internal compartment of flexor tendons are subjected to cyclic mechanical load as muscle contracts to move limbs or digits. Tendons are largely tensile load bearing tissues and are highly matrix intensive with nondividing cells providing maintenance functions. However, when an injury occurs, tendon cells are stimulated to divide by activated endogenous growth factors and those from platelets and plasma. We hypothesize that tendon cells detect mechanical load signals but do not interpret such signals as mitogenic unless an active growth factor is present. We have used an in vitro mechanical load model, application of cyclic strain to cells cultured on flexible bottomed culture plates, to test the hypothesis that tendon cells require platelet-derived growth factor (PDGF-BB) and insulin-like growth factor-I(IGF-I) in addition to mechanical load to stimulate DNA synthesis. In addition, we demonstrate that in avian tendon cells, load and growth factors stimulate phosphorylation of tyrosine residues in multiple proteins, including pp60src, a protein kinase that phosphorylates receptor protein tyrosine kinases. A lack of mitogenic responsiveness to mechanical load alone by tendon cells may be a characteristic of a regulatory pathway that modulates cell division.

Authors
Banes, AJ; Tsuzaki, M; Hu, P; Brigman, B; Brown, T; Almekinders, L; Lawrence, WT; Fischer, T
MLA Citation
Banes, AJ, Tsuzaki, M, Hu, P, Brigman, B, Brown, T, Almekinders, L, Lawrence, WT, and Fischer, T. "PDGF-BB, IGF-I and mechanical load stimulate DNA synthesis in avian tendon fibroblasts in vitro." Journal of Biomechanics 28.12 (1995): 1505-1513.
PMID
8666590
Source
scival
Published In
Journal of Biomechanics
Volume
28
Issue
12
Publish Date
1995
Start Page
1505
End Page
1513
DOI
10.1016/0021-9290(95)00098-4

Mechanoreception at the cellular level: the detection, interpretation, and diversity of responses to mechanical signals.

Cells from diverse tissues detect mechanical load signals by similar mechanisms but respond differently. The diversity of responses reflects the genotype of the cell and the mechanical demands of the resident tissue. We hypothesize that cells maintain a basal equilibrium stress state that is a function of the number and quality of focal adhesions, the polymerization state of the cytoskeleton, and the amount of extrinsic, applied mechanical deformation. A load stimulus detected by a mechano-electrochemical sensory system, including mechanically sensitive ion channels, integrin-cytoskeleton machinery, and (or) a load-conformation sensitive receptor or nonreceptor tyrosine kinase, may activate G proteins, induce second messengers, and activate an RPTK or JAK/STAT kinase cascade to elicit a response. We propose the terms autobaric to describe a self-loading process, whereby a cell increases its stress state by contracting and applying a mechanical load to itself, and parabaric, whereby a cell applies a load to an adjacent cell by direct contact or through the matrix. We predict that the setpoint for maintaining this basal stress state is affected by continuity of incoming mechanical signals as deformations that activate signalling pathways. A displacement of the cytoskeletal machinery may result in a conformational change in a kinase that results in autophosphorylation and cascade initiation. pp60Src is such a kinase and is part of a mechanosensory protein complex linking integrins with the cytoskeleton. Cyclic mechanical load induces rapid Src phosphorylation. Regulation of the extent of kinase activation in the pathway(s) may be controlled by modulators such as G proteins, kinase phosphorylation and activation, and kinase inhibitors or phosphatases. Intervention at the point of ras-raf interaction may be particularly important as a restriction point.

Authors
Banes, AJ; Tsuzaki, M; Yamamoto, J; Fischer, T; Brigman, B; Brown, T; Miller, L
MLA Citation
Banes, AJ, Tsuzaki, M, Yamamoto, J, Fischer, T, Brigman, B, Brown, T, and Miller, L. "Mechanoreception at the cellular level: the detection, interpretation, and diversity of responses to mechanical signals." Biochemistry and cell biology = Biochimie et biologie cellulaire 73.7-8 (1995): 349-365.
PMID
8703408
Source
scival
Published In
Biochemistry and Cell Biology
Volume
73
Issue
7-8
Publish Date
1995
Start Page
349
End Page
365

Fibronectin in the tendon-synovial complex: Quantitation in vivo and in vitro by ELISA and relative mRNA levels by polymerase chain reaction and northern blot

An enzyme-linked immunosorbent assay was used to quantitate fibronectin (Fn) levels in the outer synovia (epitenon) and internal fibrous portion (endotenon) of chicken flexor tendon and sheath. Primary cell cultures from these tissues and their secretions also were assayed for Fn levels. The polymerase chain reaction (PCR) was used to determine relative steady-state levels of Fn mRNA in primary cultures of synovial and internal fibroblasts from chicken tendon, and Northern blot analysis was performed to verify relative levels of the Fn message. The epitenon contained 3.8-fold more Fn than did the endotenon, and the sheath synovium contained 21-fold more Fn than did the internal fibrous portion of sheath. Cells cultured from the epitenon produced 9.3 and 13-fold more cell-associated and secreted Fn, respectively, than did cultured endotenon fibroblasts. Sheath synovial cells produced 17 and 3.2-fold more cell-associated and secreted Fn, respectively, than did sheath internal fibroblasts. Levels of Fn mRNA, as measured by PCR and Northern blot, were 1.6 and 1.8-fold greater, respectively, in tendon synovial cells compared with tendon internal fibroblasts. The biologic reason for increased Fn in tendon synovium is not known. We theorize that Fn may stabilize tendon synovium to shear stress and may play a role in the modulation of synovial rheology in the normal tendon. In the injured tendon, Fn may be involved in the organization of collagen deposition or may act through association with growth factors to aid healing.

Authors
Brigman, BE; Hu, P; Yin, H; Tsuzaki, M; Lawrence, WT; Banes, AJ
MLA Citation
Brigman, BE, Hu, P, Yin, H, Tsuzaki, M, Lawrence, WT, and Banes, AJ. "Fibronectin in the tendon-synovial complex: Quantitation in vivo and in vitro by ELISA and relative mRNA levels by polymerase chain reaction and northern blot." Journal of Orthopaedic Research 12.2 (1994): 253-261.
PMID
8164099
Source
scival
Published In
Journal of Orthopaedic Research
Volume
12
Issue
2
Publish Date
1994
Start Page
253
End Page
261
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