Arminder Kaura

Global adverse event reports of breast implant-Associated ALCL: An international review of 40 government authority databases

Background: Tracking world cases of breast implant–associated anaplastic large cell lymphoma (ALCL) is currently limited to patient registries at a few academic centers, dependent upon patient referral and case reports in the literature. The purpose of this study was to review and compare federal database adverse event reports of breast implant–associated ALCL encompassing the major breast implant markets worldwide. Methods: Federal implantable device regulatory bodies were contacted and database queries were performed for 40 countries. Demographics, device characteristics, pathology, treatment modalities, and outcomes were assessed when available. Results: For the countries queried, 363 unique cases were reported for breast implant–associated ALCL. Search terms “anaplastic” and “ALCL” were queried of the U.S. Manufacturer and User Facility Device Experience (MAUDE) database and yielded 258 unique cases as of September 2015, of which only 130 had pathologic markers performed. Implant surface was textured significantly more than smooth (50 percent versus 4.2 percent; p = 0.0001). Treatment, when reported (n = 136), included explantation [n = 125 (91.9 percent)], chemotherapy [n = 42 (30.8 percent)], radiation therapy [n = 25 (18.4 percent)], and/or stem cell transplant [n = 9 (6.6 percent)], and five deaths were reported. Conclusions: Federal reporting of breast implant–associated ALCL has limitations in providing clinical history, treatment, and oncologic follow-up. Worldwide and country-specific total and textured implant sales data are needed to determine critical incidence and prevalence analysis. International multi-institutional collaborations and centralized tissue consortiums working in concert with federal authorities are necessary to acquire accurate complete data on breast implant–associated ALCL.

High-frequency spectral ultrasound imaging (SUSI) visualizes early post-traumatic heterotopic ossification (HO) in a mouse model

PURPOSE Early treatment of heterotopic ossification (HO) is currently limited by delayed diagnosis due to limited visualization at early time points. In this study, we validate the use of spectral ultrasound imaging (SUSI) in an animal model to detect HO as early as one week after burn tenotomy. METHODS Concurrent SUSI, micro CT, and histology at 1, 2, 4, and 9weeks post-injury were used to follow the progression of HO after an Achilles tenotomy and 30% total body surface area burn (n=3-5 limbs per time point). To compare the use of SUSI in different types of injury models, mice (n=5 per group) underwent either burn/tenotomy or skin incision injury and were imaged using a 55MHz probe on VisualSonics VEVO 770 system at one week post injury to evaluate the ability of SUSI to distinguish between edema and HO. Average acoustic concentration (AAC) and average scatterer diameter (ASD) were calculated for each ultrasound image frame. Micro CT was used to calculate the total volume of HO. Histology was used to confirm bone formation. RESULTS Using SUSI, HO was visualized as early as 1week after injury. HO was visualized earliest by 4weeks after injury by micro CT. The average acoustic concentration of HO was 33% more than that of the control limb (n=5). Spectroscopic foci of HO present at 1week that persisted throughout all time points correlated with the HO present at 9weeks on micro CT imaging. CONCLUSION SUSI visualizes HO as early as one week after injury in an animal model. SUSI represents a new imaging modality with promise for early diagnosis of HO.

Evaluation of Salivary Cytokines for Diagnosis of both Trauma-Induced and Genetic Heterotopic Ossification

Purpose Heterotopic ossification (HO) occurs in the setting of persistent systemic inflammation. The identification of reliable biomarkers can serve as an early diagnostic tool for HO, especially given the current lack of effective treatment strategies. Although serum biomarkers have great utility, they can be inappropriate or ineffective in traumatic acute injuries and in patients with fibrodysplasia ossificans progressiva (FOP). Therefore, the goal of this study is to profile the cytokines associated with HO using a different non-invasive source of biomarkers. Methods Serum and saliva were collected from a model of trauma-induced HO (tHO) with hind limb Achilles’ tenotomy and dorsal burn injury at indicated time points (pre-injury, 48 h, 1 week, and 3 weeks post-injury) and a genetic non-trauma HO model (Nfatc1-Cre/caAcvr1fl/wt). Samples were analyzed for 27 cytokines using the Bio-Plex assay. Histologic evaluation was performed in Nfatc1-Cre/caAcvr1fl/wt mice and at 48 h and 1 week post-injury in burn tenotomy mice. The mRNA expression levels of these cytokines at the tenotomy site were also quantified with quantitative real-time PCR. Pearson correlation coefficient was assessed between saliva and serum. Results Levels of TNF-α and IL-1β peaked at 48 h and 1 week post-injury in the burn/tenotomy cohort, and these values were significantly higher when compared with both uninjured (p < 0.01, p < 0.03) and burn-only mice (p < 0.01, p < 0.01). Immunofluorescence staining confirmed enhanced expression of IL-1β, TNF-α, and MCP-1 at the tenotomy site 48 h after injury. Monocyte chemoattractant protein-1 (MCP-1) and VEGF was detected in saliva showing elevated levels at 1 week post-injury in our tHO model when compared with both uninjured (p < 0.001, p < 0.01) and burn-only mice (p < 0.005, p < 0.01). The Pearson correlation between serum MCP-1 and salivary MCP-1 was statistically significant (r = 0.9686, p < 0.001) Similarly, the Pearson correlation between serum VEGF and salivary VEGF was statistically significant (r = 0.9709, p < 0.05). Conclusion In this preliminary study, we characterized the diagnostic potential of specific salivary cytokines that may serve as biomarkers for an early-stage diagnosis of HO. This study identified two candidate biomarkers for further study and suggests a novel method for diagnosis in the context of current difficult diagnosis and risks of current diagnostic methods in certain patients.

Abstract 46. Modulating TAK1 Signaling to Enhance Scaffold and Cell-Free Calvarial Healing

T ueday, M arch 8, 2017 METHODS: One hundred fifty-eight patients with 277 expanded skin cases during 2010 to 2014 were reviewed and photograph-evaluated for the expanded skin texture and regenerative condition. Overall texture of the expanded skin flaps (Good, Fair, Poor) were evaluated and documented by senior attending surgeons. The occurrence of five indications of skin regeneration limitation, including skin thickness, skin color, stretch mark, vessel varicose and skin lesion, during skin expansion were recorded. The correlation of indications to overall skin regeneration condition was statistically analyzed.

Abstract 96: Identification and Therapeutic Targeting of a Central DNA-Based Mechanism Through Which Movement Augments Inflammation

RESULTS: Flow cytometry demonstrated that genetic loss of scleraxis among mesenchymal cells significantly reduced the presence of macrophages (F4/80+) and neutrophils (Cd11b+Ly6G+) at the injury site within 48 hours after injury. The presence of PDGFRa+ mesenchymal cells was also significantly reduced based on both flow cytometry and histologic analysis. These findings were confirmed with ciprofloxacin treatment. Furthermore, genetic loss of Scleraxis and ciprofloxacin both corresponded with a significant reduction in mesenchymal cell proliferation. Ciprofloxacin treatment led to reduced chondrogenic differentiation and aggrecan expression. Genetic loss of Scleraxis reduced ectopic cartilage formation when compared with wild type controls.

Abstract 54: Spectroscopic Ultrasound Visualizes Early Heterotopic Ossification

RESULTS: Axon counts clearly demonstrated disproportionately reduced regeneration in the longer graft compared to the short graft when measuring at equivalent distances to the spinal cord: the number of regenerated axons in the long graft was 57% of those regenerated in the short graft. Additionally, retrograde labeling showed significantly fewer motoneurons were found to be regenerating axons to long grafts compared to the short graft repairs. Cell composition amongst the different grafts and injured nerve were surprisingly consistent: groups had similar total numbers of cells and similar proportions of fibroblasts, Schwann cells, and macrophages. Immunohistochemical analysis showed an increased percentage of cells with senescent markers in the long grafts and in the “normal” nerve proximal to the graft. While gene expression for senescent markers was increased in both long and short nerve grafts, these markers remained elevated over time in the long grafts. Interestingly, GDNF and IL-6 expression was elevated in the long grafts compared to the short. Finally, immunohistochemistry revealed increased NOTCH signalling in the long grafts. CONCLUSION: Comparison of short and long grafts, at points equidistant to the spinal cord, showed reduced axon regeneration and reduced number of motoneurons regenerating axons. Given this reduced regeneration in the presence of a long graft and the finding that cellular composition was unchanged, immunohistochemistry and gene expression were used to identify gene and protein expression differences in the grafts.The longer grafts were found to have a greater proportion of senescent cells and the nerve proximal to the graft even showed senescent changes. Gene expression associated with senescent was increased in the grafts but retained over time in the longer grafts. Prior work has linked increased NOTCH signalling to reduced neurite extension from dorsal root ganglia neurons and the current work links increasing graft length with increased NOTCH signalling. These protein and gene expression changes give insight as to the poor clinical outcomes associated with autografts and provide targets for improvement.

Abstract 2: Macrophage-specific TGF-B is a Targetable Cytokine to Prevent Heterotopic Ossification

PURPOSE: Lymphedema is a common, life-long complication of cancer treatment that currently has no cure. Patients with lymphedema have decreased quality of life and suffer recurrent infections, while current treatments are merely palliative and designed to prevent disease progression. Accumulating evidence indicates that T cells play a key role in the pathology of lymphedema by inhibiting lymphangiogenesis and promoting tissue fibrosis. Because the pathophysiology of lymphedema involves primarily the skin and subcutaneous tissues, it may be possible to target T cells locally using topical medications such as tacrolimus without inducing systemic immunosuppression. The purpose of this study was therefore to study the efficacy of topical tacrolimus for prevention and treatment of lymphedema using preclinical mouse models.

Abstract 95: Inhibition of Scleraxis Signaling Provides a Target to Reduce Mesenchymal Cell Inflammation During Wound Healing

PURPOSE: Impaired wound healing is a serious complication and impacts patient’s quality of life adversely. Among extracellular matrix (ECM) molecules, hyaluronan (HA) has been suggested to play a critical role in all phases of wound healing as it modulates cell behavior including adhesion, migration, proliferation, metabolism and differentiation. HA is produced by 3 distinct hyaluronan synthesis (Has) and exists in varying sizes. It is widely accepted that large molecular weight HA is involved in structural and anti-inflammatory functions, whereas small molecular weight HA is angiogenetic and pro-inflammatory.

Abstract 10: Use of a Novel MicroRNA-519c Construct for Targeted Downregulation of Hypoxia Inducible Factor 1 (Hif-1α)

PURPOSE: Heterotopic Ossification (HO) is the abnormal formation of ectopic bone after trauma or thermal injury. Hypoxia-inducible factor-1 alpha (Hif-1α) is a critical mediator of this process. We have previously demonstrated that loss of Hif-1α in a transgenic mouse model decreases HO. Building on these findings, the goal of the current study is to use targeted inhibition of Hif-1α to decrease HO formation. MicroRNAs (miRNA) are emerging in the field of cancer research as an important method of specific and targeted intervention given their unique ability to modulate protein translation without the severe side effects common to more ubiquitous modalities of treatment. In this study, we introduce the novel formulation of miRNA within a polymer sphere vehicle as a therapeutic option for HO that improves delivery and selectivity compared to other available alternatives. We validate the efficacy of this novel polymermicroRNA polyplex to downregulate Hif-1α and vascular endothelial growth factor (VEGF) to serve as a potential pharmacologic antagonist against HO in a targeted fashion.

Abstract 16: Inhibition of mTOR Signaling Reduces Mesenchymal Cell Migration To Sites Of Injury And Eliminates Heterotopic Ossification In A Mouse Model

INTRODUCTION: Several experimental studies suggest that growth hormone-based therapies have the potential to accelerate and augment axonal regeneration while simultaneously act directly on muscle and Schwann cells (SCs) to minimize denervation atrophy prior to re-innervation. The purpose of this study was to assess the impact of growth hormone (GH) therapy on preventing the deleterious effects of chronic denervation (CD) injury on nerve regeneration and resulting muscle function. We hypothesized that systemic GH therapy can maintain chronically-denervated muscle and SCs, accelerate axonal regeneration, and improve murine extremity function in the setting of chronic denervation (CD) by preserving muscle mass and promoting motor reinnervation.