Publications by authors named "Peter Evangelista"

16 Publications

  • Page 1 of 1

Burn scar regeneration with the "SUFA" (Subcision and Fat Grafting) technique. A prospective clinical study.

JPRAS Open 2018 Sep 22;17:5-8. Epub 2018 May 22.

Division of Plastic Surgery, The Warren Alpert Medical School of Brown University, Richmond St., Providence, RI, United States.

Background: Treatment of burn scars with traditional surgical techniques is challenging due to recurrent contractures. Fat grafting has been previously used in small clinical series and results are often biased by lack of scientific validating methods. Fat grafting in clinical practice is often evaluated for its filler properties and rarely scientifically validated for its potential in dermal regeneration. Animal studies have shown dermal regeneration with new deposition and reorientation of the collagen fiber. Our study aims to apply the validity of in vitro studies to clinical practice.

Methods: Our study prospectively evaluated outcomes in 12 patients treated with the "SUFA" technique (Subcision and Fat Grafting) for debilitating contracted burns scars limiting range of motion. Results were evaluated clinically with the Vancouver scale and by range of motion at 1, 3, 6 and 12 months. Dermal regeneration was evaluated by looking at dermis thickening using high definition ultrasound and scar remodeling looking at reorientation and new deposition of collagen fibers with hematoxylin-eosin histology and monoclonal antibodies against collagen type 1 and 3.

Results: Statistically significant clinical improvements in range of motion of the affected joints was observed (<0.05). Fat reabsorption occurred with a mean of 40%. Thickening of dermis and redistribution and reorientation of the collagen fibers within the dermis was also demonstrated.

Conclusions: Our results present the first clinical scientific evidence of dermal regeneration in fat grafting. Using monoclonal antibodies and high definition ultrasounds, we demonstrate the first evidence of dermis regeneration in a clinical scenario.
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http://dx.doi.org/10.1016/j.jpra.2018.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7061675PMC
September 2018

Clinical Outcomes of Nonunions of Hindfoot and Ankle Fusions.

J Bone Joint Surg Am 2016 Dec;98(23):2006-2016

1Department of Orthopaedic Surgery, Inselspital, University of Bern, Bern, Switzerland 2Department of Orthopaedics, University of British Columbia, Vancouver, British Columbia, Canada 3BC's Foot and Ankle Clinic, St. Paul's Hospital, Vancouver, British Columbia, Canada 4Department of Orthopaedics, University of Rochester School of Medicine and Dentistry, Rochester, New York 5Division of Orthopaedic Surgery, St. Michael's Hospital and University of Toronto, Toronto, Ontario, Canada 6Dalhousie University, Halifax, Nova Scotia, Canada 7Queen Elizabeth II Health Sciences Center, Halifax, Nova Scotia, Canada 8Division of Foot and Ankle Surgery, Department of Orthopaedic Surgery, Massachusetts General Hospital and Newton-Wellesley Hospital, Waltham, Massachusetts 9Department of Orthopaedic Surgery and Rehabilitation, Loyola University Health System, Maywood, Illinois 10Foot & Ankle Service, Department of Trauma & Orthopaedics, Tan Tock Seng Hospital, Singapore 11Wright Medical N.V., Franklin, Tennessee.

Background: While nonunion after foot and ankle fusion surgery has been associated with poor outcomes, we are not aware of any longitudinal study on this subject. Thus, we prospectively evaluated the impact of nonunion on clinical outcomes of foot and ankle fusions and identified potential risk factors for nonunion after these procedures.

Methods: Using data from a randomized clinical trial on recombinant human platelet-derived growth factor-BB (rhPDGF-BB; Augment Bone Graft, BioMimetic Therapeutics), union was defined either by assessment of computed tomography (CT) scans at 24 weeks by a reviewer blinded to the type of treatment or by the surgeon's composite assessment of clinical and radiographic findings at 52 weeks and CT findings at 24 or 36 weeks. The nonunion and union groups (defined with each assessment) were then compared in terms of clinical outcome scores on the American Orthopaedic Foot & Ankle Society Ankle-Hindfoot Scale (AOFAS-AHS), Foot Function Index (FFI), and Short Form-12 (SF-12) as well as age, sex, body mass index (BMI), smoking status, diabetes status, work status, and arthrodesis site.

Results: Blinded CT assessment identified nonunion in 67 (18%) of 370 patients, and surgeon assessment found nonunion in 21 (5%) of 389 patients. Postoperatively, the nonunion group scored worse than the union group, regardless of the method used to define the nonunion, on the AOFAS-AHS and FFI, with mean differences of 10 and 12 points, respectively, when nonunion was determined by blinded CT assessment and 19 and 20 points when it was assessed by the surgeon. The nonunion group also had worse SF-12 Physical Component Summary scores. Differences between the union and nonunion groups were clinically meaningful for all outcome measures, regardless of the nonunion assessment method. The concept of an asymptomatic nonunion (i.e., imaging indicating nonunion but the patient doing well) was not supported. Patients with nonunion were more likely to be overweight, smokers, and not working.

Conclusions: This prospective longitudinal study demonstrated poorer functional outcomes in patients with a nonunion after foot and ankle fusion, regardless of whether the diagnosis of nonunion was based on CT only or on combined clinical, radiographic, and CT assessment.

Level Of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.
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http://dx.doi.org/10.2106/JBJS.14.00872DOI Listing
December 2016

The Importance of Sufficient Graft Material in Achieving Foot or Ankle Fusion.

J Bone Joint Surg Am 2016 Aug;98(15):1260-7

Department of Orthopaedics, University of Rochester School of Medicine and Dentistry, Rochester, New York.

Background: Nonunion, an important complication following foot and ankle arthrodesis, causes substantial morbidity and disability. In patients undergoing hindfoot and ankle arthrodesis, autogenous bone graft (autograft) or a suitable alternative is often used to promote osseous fusion across the joint. This study assessed the importance of adequate graft material in the fusion space to achieve joint fusion during ankle and hindfoot arthrodesis.

Methods: This study used data from a previously published clinical trial of grafting material (recombinant human platelet-derived growth factor-BB with beta-tricalcium phosphate [rhPDGF-BB/β-TCP] or autograft) for healing in hindfoot and ankle arthrodesis to correlate the amount of graft fill at 9 weeks with ultimate healing. Patients who received supplemental graft material for ankle or hindfoot arthrodesis for end-stage ankle or hindfoot arthritis were stratified according to nonunion risk factors and surgical fusion site. Patients underwent arthrodesis using standard rigid internal fixation. Graft fill was defined as "adequate" if the material occupied ≥50% of the cross-sectional area of the fusion space on a computed tomography (CT) scan made at 9 weeks. Fusion was defined as osseous bridging of ≥50% of each articulation on a CT scan made at 24 weeks. Three hundred and seventy-nine patients with 573 joints (383 managed with rhPDGF-BB/β-TCP and 190 managed with autograft) that underwent arthrodesis had complete follow-up with 9-week and 24-week CT scans available.

Results: Overall, 472 (82%) of 573 joints had adequate graft fill; of those, 383 (81%) were successfully fused at 24 weeks compared with 21 (21%) of 101 joints without adequate graft fill (p < 0.0001). Absolute fusion rate differences (joints with adequate fill minus those without adequate fill) were consistent across joints (61% to 63%) and for graft materials. The overall odds ratio (OR) of successful fusion in joints with adequate graft fill compared with those without adequate graft fill was 16.4 (95% confidence interval, 9.6 to 27.9).

Conclusions: This study demonstrates an association between the amount of graft material and successful hindfoot and ankle arthrodesis. Graft material filling of ≥50% of the fusion space at 9 weeks, regardless of type or origin, was associated with significantly higher fusion rates at 24 weeks.

Level Of Evidence: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.
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http://dx.doi.org/10.2106/JBJS.15.00879DOI Listing
August 2016

Stress fracture of the second metatarsal and sprain of lisfranc joint in a pre-professional ballet dancer.

J Dance Med Sci 2015 Jun;19(2):80-5

Department of Orthopaedic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

We present the case of a 14-year-old pre-professional ballerina that demonstrates common features of two conditions affecting the midfoot that are often missed or subject to delay in diagnosis in such young athletes: 1. stress fractures at the base of the second metatarsal, and 2. sprain of the Lisfranc joint complex. While these represent potentially career-altering injuries in the professional dancer, this case demonstrates that a high index of clinical suspicion, careful physical exam, appropriate radiographic assessment, and prompt treatment are essential to achieving the best possible outcome.
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http://dx.doi.org/10.12678/1089-313X.19.2.80DOI Listing
June 2015

Prospective Randomized Controlled Trial of Hindfoot and Ankle Fusions Treated With rhPDGF-BB in Combination With a β-TCP-Collagen Matrix.

Foot Ankle Int 2015 Jul 6;36(7):739-48. Epub 2015 Apr 6.

Department of Orthopaedic Surgery, Massachusetts General Hospital, Boston, MA, USA.

Background: Ankle and hindfoot arthrodesis is often supplemented with autograft to promote bony union. Autograft harvest can lead to increased perioperative morbidity. Purified recombinant human platelet-derived growth factor BB homodimer (rhPDGF-BB) has stimulated bone formation in mandibular defects and hindfoot fusion. This randomized controlled trial evaluated the efficacy and safety of rhPDGF-BB combined with an injectable, osteoconductive beta-tricalcium phosphate (β-TCP)-collagen matrix versus autograft in ankle and hindfoot fusions.

Methods: Seventy-five patients requiring ankle or hindfoot fusion were randomized 5:1 for rhPDGF-BB/β-TCP-collagen (treatment, n = 63) or autograft (control, n = 12). Prospective analysis included 142 autograft control subjects from another clinical trial with identical study protocols. Standardized operative and postoperative protocols were used. Patients underwent standard internal fixation augmented with autograft or 0.3 mg/mL rhPDGF-BB/β-TCP-collagen. Radiologic, clinical, and quality-of-life outcomes were assessed over 52 weeks. Primary outcome was joint fusion (50% or more osseous bridging on computed tomography) at 24 weeks. Secondary outcomes included radiographs, clinical healing status, visual analog scale pain score, American Orthopaedic Foot & Ankle Society Ankle-Hindfoot Scale score, Foot Function Index score, and Short Form-12 score. Noninferiority P values were calculated.

Results: Complete fusion of all involved joints at 24 weeks as indicated by computed tomography was achieved in 53 of 63 (84%) rhPDGF-BB/β-TCP-collagen-treated patients and 100 of 154 (65%) autograft-treated patients (P < .001). Mean time to fusion was 14.3 ± 8.9 weeks for rhPDGF-BB/β-TCP-collagen patients versus 19.7 ± 11.5 weeks for autograft patients (P < .01). Clinical success at 52 weeks was achieved in 57 of 63 (91%) rhPDGF-BB/β-TCP-collagen patients and 120 of 154 (78%) autograft patients (P < .001). Safety-related outcomes were equivalent. Autograft controls had 2 bone graft harvest infections.

Conclusions: Application of rhPDGF-BB/β-TCP-collagen was a safe, effective alternative to autograft for ankle and hindfoot fusions, eliminating the pain and morbidity associated with autograft harvesting.

Level Of Evidence: Level I, prospective randomized study.
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http://dx.doi.org/10.1177/1071100715576370DOI Listing
July 2015

Rapid-Onset Diffuse Skeletal Fluorosis from Inhalant Abuse: A Case Report.

JBJS Case Connect 2014 Oct/Dec/Nov;4(4):e108

Departments of Orthopedics (E.C., R.Y.H., R.A., and L.E.R.) and Diagnostic Imaging (P.E.), Brown Alpert Medical School/Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903. E-mail address for E. Cohen:

Case: A thirty-year-old man presented with severely debilitating left hip pain and stiffness. Radiographs demonstrated diffuse osteosclerosis and heterotopic bone formation with near ankylosis of the left hip. The patient underwent successful joint-preserving surgery to restore hip range of motion. After disclosing a history of inhalant abuse, which was confirmed by elevated serum fluoride levels, he was diagnosed with diffuse skeletal fluorosis.

Conclusions: To the best of our knowledge, we present the first reported case of diffuse skeletal fluorosis caused by inhalant abuse of 1,1-difluoroethane. Skeletal fluorosis is uncommon in the United States but is important to consider in the differential diagnosis when a patient presents with otherwise unexplained joint pain and osteosclerosis.
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http://dx.doi.org/10.2106/JBJS.CC.N.00085DOI Listing
December 2017

The effect of medial and lateral calcaneal osteotomies on the tarsal tunnel.

Foot Ankle Int 2014 Apr 13;35(4):383-8. Epub 2014 Jan 13.

Department of Orthopedics, Warren Alpert School of Medicine at Brown University, Providence, RI, USA.

Background: As an entrapment phenomenon, tarsal tunnel syndrome has been described after calcaneal osteotomy, and since the tibial nerve has also been shown to be very sensitive to ankle position, position of the calcaneus after osteotomy and displacement was thought to likely influence the environment of the tibial nerve within the tarsal canal. The respective volume of the tarsal canal was therefore hypothesized to decrease with medial or lateral displacement osteotomies of the calcaneus.

Methods: Anterior and posterior calcaneal osteotomies were made in cadaveric matched pairs and brought through sequential medial and lateral displacements. Magnetic resonance imaging was used to estimate the comparative resultant volume of the tarsal canal after each of these new positions were assumed, as compared with baseline. The proximity of the osteotomy cut to the nerve's location was also measured.

Results: The tarsal tunnel volume was calculated for all 5 displacement states and were as follows: far-lateral (9506 mm(3)), near-lateral (10 073 mm(3)), normal (11 839 mm(3)), near-medial (11 489 mm(3)), and far-medial (11 760 mm(3)). No significant difference in tarsal tunnel volume was identified between the normal, nondisplaced specimens in the anterior or posterior groups (11 954 mm(3) vs 11 809 mm(3)). No difference in tarsal tunnel volume was identified between the anterior and posterior osteotomies at any of the 4 displacements. The distance from tibial nerve to the medial exit site of the osteotomy was found to be significantly less in the anterior group compared to the posterior group (4 mm vs 14.2 mm, P < .0001).

Conclusion: Lateral, but not medial, osteotomy fragment displacement results in significant reduction of tarsal tunnel volume. The location of the cut does not seem to affect any substantive change in volume. Anteriorly placed osteotomies appear to jeopardize the neurovascular structures more than posteriorly placed osteotomies.

Clinical Relevance: These findings provide surgeons with clinical evidence in support of performing a prophylactic tarsal tunnel release for patients undergoing lateralizing calcaneal osteotomies.
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http://dx.doi.org/10.1177/1071100713519599DOI Listing
April 2014

Establishing the relationship between clinical outcome and extent of osseous bridging between computed tomography assessment in isolated hindfoot and ankle fusions.

Foot Ankle Int 2013 Dec 16;34(12):1612-8. Epub 2013 Sep 16.

Dalhousie University, Halifax, NS, Canada.

Background: Determining the success of joint fusion operations is often a diagnostic dilemma, and many factors may be considered. Most would agree that the broad categories of clinical success and radiographic success are likely most useful to determine the overall success of a joint fusion operation. Very little evidence exists to assist the surgeon in determining what constitutes a successful radiographic fusion. The aim of this study was to determine the extent of osseous bridging as measured by computed tomography (CT) that was associated with a good clinical outcome as measured by the 12-Item Short Form (SF-12), Foot Function Index (FFI), and American Orthopaedic Foot & Ankle Society (AOFAS) clinical outcomes questionnaires at 24 weeks.

Methods: Patients who had isolated joint fusions were evaluated (n = 275) to determine the correlation of extent of osseous bridging with clinical outcome. The extent of osseous bridging across the joint in question was categorized as absent (0%-24%), minimal (25%-49%) moderate (50%-74%), or complete (75%-100%). Clinical outcome scores included the SF-12, FFI, and AOFAS outcomes score.

Results: Patients evaluated to have at least minimal osseous bridging at fusion sites (25%-49%) on CT reported a clinically important improvement in SF-12, FFI, and AOFAS, whereas those with "absent" osseous bridging (0%-24%) did not report a clinically important improvement in outcome scores.

Conclusion: This study suggests that osseous bridging of greater than 25% to 49% at the fusion site measured by CT may be necessary to consider a hindfoot or ankle fusion clinically successful.

Level Of Evidence: Level IV, case series.
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http://dx.doi.org/10.1177/1071100713504746DOI Listing
December 2013

Recombinant human platelet-derived growth factor-BB and beta-tricalcium phosphate (rhPDGF-BB/β-TCP): an alternative to autogenous bone graft.

J Bone Joint Surg Am 2013 Jul;95(13):1184-92

Department of Orthopaedic Surgery, The Warren Alpert School of Medicine at Brown University, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903, USA.

Background: Joint arthrodesis employing autogenous bone graft (autograft) remains a mainstay in the treatment of many foot and ankle problems. However, graft harvest can lead to perioperative morbidity and increased cost. We tested the hypothesis that purified recombinant human platelet-derived growth factor-BB (rhPDGF-BB) homodimer combined with an osteoconductive matrix (beta-tricalcium phosphate [β-TCP]) would be a safe and effective alternative to autograft.

Methods: A total of 434 patients were enrolled in thirty-seven clinical sites across North America in a prospective, randomized (2:1), controlled, non-inferiority clinical trial to compare the safety and efficacy of the combination rhPDGF-BB and β-TCP with those of autograft in patients requiring hindfoot or ankle arthrodesis. Radiographic, clinical, functional, and quality-of-life end points were assessed through fifty-two weeks postoperatively.

Results: Two hundred and sixty patients (394 joints) underwent arthrodesis with use of rhPDGF-BB/β-TCP. One hundred and thirty-seven patients (203 joints) underwent arthrodesis with use of autograft. With regard to the primary end point, 159 patients (61.2% [262 joints (66.5%)]) in the rhPDGF-BB/β-TCP group and eighty-five patients (62.0% [127 joints (62.6%)]) in the autograft group were fused as determined by computed tomography at six months (p < 0.05). Clinically, 224 patients (86.2%) [348 joints (88.3%)]) in the rhPDGF-BB/β-TCP group were considered healed at fifty-two weeks, compared with 120 patients (87.6% [177 joints (87.2%)] in the autograft group (p = 0.008). Overall, fourteen of sixteen secondary end points at twenty-four weeks and fifteen of sixteen secondary end points at fifty-two weeks demonstrated statistical non-inferiority between the groups, and patients in the rhPDGF-BB/β-TCP group were found to have less pain and an improved safety profile.

Conclusions: In patients requiring hindfoot or ankle arthrodesis, treatment with rhPDGF-BB/β-TCP resulted in comparable fusion rates, less pain, and fewer side effects as compared with treatment with autograft.
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http://dx.doi.org/10.2106/JBJS.K.01422DOI Listing
July 2013

Predicting pulmonary embolus in orthopedic trauma patients using the Wells score.

Orthopedics 2013 May;36(5):e642-7

Division of Orthopaedic Trauma, Department of Orthopaedics, Warren Alpert Medical School, Brown University, 593 Eddy St, Providence, RI 02903, USA.

The decision to perform computed tomography pulmonary angiography (CTPA) to rule out pulmonary embolism (PE) in orthopedic trauma patients is challenging. The Wells score is a commonly used clinical probability tool developed to determine the likelihood of PE and assist in determining the need for CTPA examination. This study evaluated the usefulness of the Wells score for predicting PE in patients admitted to the orthopedic trauma service. All patients who were admitted to the orthopedic trauma service at the authors' institution between 2001 and 2011 who underwent CTPA were identified. The Wells score was calculated retrospectively for each patient, and risk categories using the traditional and alternative interpretations of the Wells score were assigned. Pulmonary embolism was diagnosed in 27 (16%) of 169 patients who underwent CTPA. In total, 27 (0.39%) of 6854 patients admitted to the orthopedic trauma service were diagnosed with PE during initial hospitalization. Mean Wells score was 3.31 (95% confidence interval, ±.28) for the entire population, 3.32 for those without PE (95% confidence interval, ±.31), and 3.28 for those with PE (95% confidence interval, ±.72) (P=.91). Average times from admission to CTPA examination for those with and without PE were 6.18 and 5.7 days, respectively (P=.94). No significant correlation existed between the Wells score and CTPA results, indicating that the Wells score is limited in predicting PE risk in orthopedic trauma patients.
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http://dx.doi.org/10.3928/01477447-20130426-29DOI Listing
May 2013

Femoroacetabular impingement.

Med Health R I 2012 May;95(5):153-4

Rhode Island Hospital, USA.

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May 2012

Atypical insufficiency type femoral stress fractures in patient on bisphosphonates.

Med Health R I 2012 Feb;95(2):61-2

Rhode Island Hospital, Providence, RI 02903, USA.

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February 2012

Pain syndrome with stress fractures in transplanted patients treated with calcineurin inhibitors.

Clin Kidney J 2012 Feb 28;5(1):13-6. Epub 2012 Jan 28.

Division of Musculoskeletal Radiology, Department of Diagnostic Imaging, Alpert Medical School of Brown University, Providence, RI, USA.

Bone disease remains a major cause of morbidity after renal transplantation. Post-transplant osseous complications include osteoporosis and osteonecrosis, both historically associated with glucocorticoids, and a newer syndrome of bone pain associated with calcineurin inhibitors. Calcineurin inhibitor-induced pain syndrome (CIPS) is a reversible etiology of lower extremity bone pain and bone marrow edema reported in patients receiving cyclosporine or tacrolimus after solid organ or bone marrow transplantation. While the syndrome's pathophysiology is unclear, bone insufficiency and epiphyseal impaction may play a role. We review the literature on this increasingly important post-transplant entity and describe a case illustrating the syndrome's key features.
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http://dx.doi.org/10.1093/ndtplus/sfr156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4400457PMC
February 2012

Prospective, randomized, multi-center feasibility trial of rhPDGF-BB versus autologous bone graft in a foot and ankle fusion model.

Foot Ankle Int 2011 Apr;32(4):344-54

University Orthopaedics, Inc., 100 Butler Dr., Providence, RI 02906, USA.

Background: The increased morbidity and surgical time associated with harvesting autologous bone graft (ABG) have encouraged surgeons to develop synthetic orthobiologic alternatives. The recombinant form of platelet-derived growth factor (rhPDGF-BB), an angiogenic, mitogenic, and chemotactic cytokine, has been shown to significantly enhance bone formation in human periodontal osseous defects when combined with a tricalcium phosphate carrier (β-TCP). The purpose of this prospective, controlled, randomized, multi-center feasibility clinical trial was to compare the safety and efficacy of this biosynthetic bone graft substitute (Augment™ Bone Graft) to ABG during ankle and hindfoot fusion.

Materials And Methods: Twenty adult subjects requiring ankle or hindfoot fusion from three U.S. centers were enrolled and randomized in a 2:1 ratio to receive Augment™ or ABG, respectively. Surgical approach and fixation techniques were standardized, and minimum followup was 9 months. The primary endpoint was radiographic osseous union, evaluated by a blinded independent radiologist. Secondary endpoints included assessment of clinical success, union rate by serial computed tomography (CT) examination, time to full weightbearing, AOFAS Ankle-Hindfoot Score (AOFAS), Foot Function Index (FFI), Short Form-12 (SF-12), and Visual Analog pain assessment Scale (Pain VAS).

Results: At 36 weeks, 77% (10/13) of the Augment™ and 50% (3/6) of the ABG patients were fused based on radiographic criteria. There were two nonunions in the Augment™ group (9%, 2/14). Healing rates based on 12 week CT scanning (50% osseous bridging) were 69% (9/13) in the Augment™ and 60% (3/5) in the ABG groups, respectively. All functional outcome measures (FFI, AOFAS, SF-12), as well as the VAS pain scores, improved in both groups over time. Surgical procedure times lasted an average 26 minutes longer for the ABG as compared to the Augment™ populations. There were no device related serious adverse events in this study.

Conclusion: Based on the available data, the rate of radiographic union, time to full weightbearing, and outcomes scores between the Augment™ and ABG subjects appear comparable. Augment™ may represent a safe and efficacious treatment alternative to ABG during foot and ankle arthrodesis.
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http://dx.doi.org/10.3113/FAI.2011.0344DOI Listing
April 2011

Conformational control inhibition of the BCR-ABL1 tyrosine kinase, including the gatekeeper T315I mutant, by the switch-control inhibitor DCC-2036.

Cancer Cell 2011 Apr;19(4):556-68

Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111, USA.

Acquired resistance to ABL1 tyrosine kinase inhibitors (TKIs) through ABL1 kinase domain mutations, particularly the gatekeeper mutant T315I, is a significant problem for patients with chronic myeloid leukemia (CML). Using structure-based drug design, we developed compounds that bind to residues (Arg386/Glu282) ABL1 uses to switch between inactive and active conformations. The lead "switch-control" inhibitor, DCC-2036, potently inhibits both unphosphorylated and phosphorylated ABL1 by inducing a type II inactive conformation, and retains efficacy against the majority of clinically relevant CML-resistance mutants, including T315I. DCC-2036 inhibits BCR-ABL1(T315I)-expressing cell lines, prolongs survival in mouse models of T315I mutant CML and B-lymphoblastic leukemia, and inhibits primary patient leukemia cells expressing T315I in vitro and in vivo, supporting its clinical development in TKI-resistant Ph(+) leukemia.
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http://dx.doi.org/10.1016/j.ccr.2011.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3077923PMC
April 2011

Best cases from the AFIP: juvenile ossifying fibroma of the calvaria.

Radiographics 2009 Jul-Aug;29(4):1195-9

Department of Diagnostic Imaging, Warren Alpert Medical School of Brown University, Rhode Island Hospital, 593 Eddy St, Providence, RI 02903, USA.

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http://dx.doi.org/10.1148/rg.294085240DOI Listing
September 2009