Browsing by Author "Brigman, Brian E"

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    ItemOpen Access
    A Fluorescence-Guided Laser Ablation System for Removal of Residual Cancer in a Mouse Model of Soft Tissue Sarcoma.
    (Theranostics, 2016) Lazarides, Alexander L; Whitley, Melodi J; Strasfeld, David B; Cardona, Diana M; Ferrer, Jorge M; Mueller, Jenna L; Fu, Henry L; Bartholf DeWitt, Suzanne; Brigman, Brian E; Ramanujam, Nimmi; Kirsch, David G; Eward, William C
    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.
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    ItemOpen Access
    Does facility volume influence survival in patients with primary malignant bone tumors of the vertebral column? A comparative cohort study.
    (The spine journal : official journal of the North American Spine Society, 2020-07) Lazarides, Alexander L; Kerr, David L; Dial, Brian L; Steele, John R; Lane, Whitney O; Blazer, Dan G; Brigman, Brian E; Mendoza-Lattes, Sergio; Erickson, Melissa M; Eward, William C

    Background context

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

    Purpose

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

    Study design

    Retrospective comparative cohort.

    Patient sample

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

    Outcome measures

    Five-year survival.

    Methods

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

    Results

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

    Conclusions

    Primary malignant BTVCs are rare, even for HVCs. Despite this, patient survival was significantly improved when treatment was performed at HVCs.
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    Epidemiologic and survival trends in adult primary bone tumors of the spine.
    (The spine journal : official journal of the North American Spine Society, 2019-12) Kerr, David L; Dial, Brian L; Lazarides, Alexander L; Catanzano, Anthony A; Lane, Whitney O; Blazer, Dan G; Brigman, Brian E; Mendoza-Lattes, Sergio; Eward, William C; Erickson, Melissa E

    Background context

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

    Purpose

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

    Study design

    Retrospective study.

    Patient sample

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

    Outcome measures

    Five-year survival.

    Methods

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

    Results

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

    Conclusions

    This study provides the most comprehensive description of the epidemiologic, treatment, and survival trends of primary bone tumors of the mobile spine. Second, patient and tumor characteristics associated with improved 5-year survival were identified using a multivariate model.
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    Preclinical Testing of a Novel Niclosamide Stearate Prodrug Therapeutic (NSPT) Shows Efficacy Against Osteosarcoma.
    (Molecular cancer therapeutics, 2020-07) Reddy, Gireesh B; Kerr, David L; Spasojevic, Ivan; Tovmasyan, Artak; Hsu, David S; Brigman, Brian E; Somarelli, Jason A; Needham, David; Eward, William C
    Therapeutic advances for osteosarcoma have stagnated over the past several decades, leading to an unmet clinical need for patients. The purpose of this study was to develop a novel therapy for osteosarcoma by reformulating and validating niclosamide, an established anthelminthic agent, as a niclosamide stearate prodrug therapeutic (NSPT). We sought to improve the low and inefficient clinical bioavailability of oral dosing, especially for the relatively hydrophobic classes of anticancer drugs. Nanoparticles were fabricated by rapid solvent shifting and verified using dynamic light scattering and UV-vis spectrophotometry. NSPT efficacy was then studied in vitro for cell viability, cell proliferation, and intracellular signaling by Western blot analysis; ex vivo pulmonary metastatic assay model; and in vivo pharmacokinetic and lung mouse metastatic model of osteosarcoma. NSPT formulation stabilizes niclosamide stearate against hydrolysis and delays enzymolysis; increases circulation in vivo with t 1/2 approximately 5 hours; reduces cell viability and cell proliferation in human and canine osteosarcoma cells in vitro at 0.2-2 μmol/L IC50; inhibits recognized growth pathways and induces apoptosis at 20 μmol/L; eliminates metastatic lesions in the ex vivo lung metastatic model; and when injected intravenously at 50 mg/kg weekly, it prevents metastatic spread in the lungs in a mouse model of osteosarcoma over 30 days. In conclusion, niclosamide was optimized for preclinical drug delivery as a unique prodrug nanoparticle injected intravenously at 50 mg/kg (1.9 mmol/L). This increased bioavailability of niclosamide in the blood stream prevented metastatic disease in the mouse. This chemotherapeutic strategy is now ready for canine trials, and if successful, will be targeted for human trials in patients with osteosarcoma.
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    The vascularized fibular graft in the pediatric upper extremity: a durable, biological solution to large oncologic defects.
    (Sarcoma, 2013-01) Zelenski, Nicki; Brigman, Brian E; Levin, L Scott; Erdmann, Detlev; Eward, William C
    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.
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    Vascularized Fibula-Based Physis Transfer: A Follow-Up Study of Longitudinal Bone Growth and Complications.
    (Plastic and reconstructive surgery. Global open, 2017-05-25) Shammas, Ronnie L; Avashia, Yash J; Farjat, Alfredo E; Catanzano, Anthony A; Levin, L Scott; Eward, William C; Brigman, Brian E; Erdmann, Detlev

    Background

    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.

    Methods

    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.

    Results

    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.

    Conclusion

    This study demonstrates that the vascularized fibula epiphyseal transfer offers the ability to preserve longitudinal limb growth and hypertrophy throughout adolescence.