How far does it go? An analysis on the extent of spinal cord injury in post-traumatic patients

Background: Spinal cord injury causes debilitating functional loss in post-trauma patients. Previous studies have showed that an area of edema (tissue damage and swelling) occurs at the level of spinal damage and may be related to the amount of functional loss in the patient and their associated recovery potential. We hypothesized that the extent of the injury is greater than previously studied and may better explain functional loss and recovery potential. Methods: We retrospectively analyzed five T2-weighted MRI spinal cord images from post-trauma patients ages 32-67. Patients had a clinically diagnosed spinal cord injury that affected the cervical segment of the spinal cord (C2-C8) and were at least 18 months post-trauma. The area of edema was evaluated through a software system, fsleyes, which allows us to interpret the extent of injury. We determined the total volume of injury and related it to the overall volume of the assessed spinal cord. Results: We observed that the extent of injury ranged across our 5 analyzed patients. We found that the percent of spinal cord damage in the cervical spinal cord ranged from 10.7% to 48.8%. Interestingly, we did not observe that the amount of spinal cord damage influenced clinical grading of functional ability in our cohort. Conclusions: Our work suggests that physical damage to the spinal cord may extend far beyond the level of injury. In subsequent analyses, we seek to define the relationship between the extent of injury and functional ability and recovery of the patient

Analysis of Secondary Neurodegeneration In Spinal Cord MRI In Post-Stroke Patients

Background: Stroke, also termed cerebral infarction, results in neurodegeneration and neuroinflammation in the brain at area of the infarct and peri-infarct regions. It has also been established that damage in the motor pathways including the corticospinal tract contribute to motor deficits in post-stroke patients. Recent research has recognized the involvement of alternate sensorimotor pathways in the spinal cord that underline disease progression and the degree of functional recovery post-stroke. Evaluating the role of alternate sensorimotor pathways in the brain can be challenging, since the pathways remained crossed until they reach the spinal cord. Although MRI has been used to examine damage in regions of the brain following a stroke, few MRI studies have been conducted to investigate neurodegeneration in the spinal cord. Creating optimal techniques to study spinal cord MRI could provide a way to better evaluate the alternate sensorimotor pathways to give way to higher prognostic methods and enhanced treatment modalities in post-stroke patients. Methods and Results: Here we review current research on spinal cord MRI imaging techniques and analysis approaches, such as, Diffusion Weighted Imaging (DWI), Spinal Cord Toolbox, Neurite Orientation Dispersion and Density Imaging (NODDI), in different neurological conditions that could be applied to analyzing post-stroke spinal cord. We summarize the advantages and limitations of each technique. Conclusion: Spinal cord imaging and analysis could provide a powerful tool to evaluate alternate sensorimotor pathways following neurological injury, in particular, stroke. Our review suggests that new analysis techniques, such as NODDI, can provide higher level specificity to understand degeneration at the level of the spinal cord. Future studies should consider utilizing spinal cord analysis to understand the role of alternate sensorimotor pathway degeneration and regeneration following a stroke

What\u27s going on with the spine? Evaluation of alternative sensorimotor degeneration post-stroke

Stroke is a leading cause of long-term disability in the United States. Previous research has shown a strong correlation between damage to the corticospinal tract (CST) and motor deficits in post-stroke patients. However, recent research suggests that other sensorimotor pathways (rubrospinal tract, medial reticulospinal tract) are damaged after stroke and may also contribute to motor dysfunction. Here, we will review current research suggesting that alternate sensorimotor pathways are involved in post-stroke motor dysfunction and outline possible avenues for future research

Spinal Cord MRI Analysis techniques in post-stroke patients

Stroke, also termed cerebral infarction, results in neurodegeneration and neuroinflammation in the brain at area of the infarct and peri-infarct regions. Recent research has shown involvement of alternate motor pathways of the spinal cord in disease progression. Creating optimal techniques to study spinal cord MRI can give way to higher prognostic methods and enhanced treatment modalities in post-stroke patients. Here, we will review current research proposing various spinal cord MRI analysis techniques in different neurological conditions that can be applied to analyzing post-stroke spinal cord

A Comparison of the Prevalence of Cirrhosis in a Hispanic and Non-Hispanic Population Based on Body Mass Index

There is a paucity of data regarding the clinical correlation of obesity and cirrhosis in a predominantly Hispanic population. Additionally, data is limited on the contribution of BMI to the incidence of liver cirrhosis in Hispanics in South Texas. The aim of this study is to assess the prevalence of liver cirrhosis and compare the prevalence between Hispanic and Non-Hispanics. In addition, these researchers seek to investigate the prevalence of liver cirrhosis stratified by body mass index. These researchers hypothesize that the prevalence of liver cirrhosis is higher amongst Hispanics than Non-Hispanics individuals, and that higher body mass index scores positively correlate with increased prevalence of liver cirrhosis

Moving toward elucidating alternative motor pathway structures post-stroke: the value of spinal cord neuroimaging

Stroke results in varying levels of motor and sensory disability that have been linked to the neurodegeneration and neuroinflammation that occur in the infarct and peri-infarct regions within the brain. Specifically, previous research has identified a key role of the corticospinal tract in motor dysfunction and motor recovery post-stroke. Of note, neuroimaging studies have utilized magnetic resonance imaging (MRI) of the brain to describe the timeline of neurodegeneration of the corticospinal tract in tandem with motor function following a stroke. However, research has suggested that alternate motor pathways may also underlie disease progression and the degree of functional recovery post-stroke. Here, we assert that expanding neuroimaging techniques beyond the brain could expand our knowledge of alternate motor pathway structure post-stroke. In the present work, we will highlight findings that suggest that alternate motor pathways contribute to post-stroke motor dysfunction and recovery, such as the reticulospinal and rubrospinal tract. Then we review imaging and electrophysiological techniques that evaluate alternate motor pathways in populations of stroke and other neurodegenerative disorders. We will then outline and describe spinal cord neuroimaging techniques being used in other neurodegenerative disorders that may provide insight into alternate motor pathways post-stroke

Abstract 553: Ibrutinib, a BTK inhibitor, impairs the generation and function of myeloid derived suppressor cells

Abstract Myeloid derived suppressor cells (MDSC) interfere with anti tumor immune responses. MDSC have also been shown to antagonize the effectiveness of immune based therapies including immune checkpoint blockade. As a result, MDSC have received attention as potential targets for immune based combination therapies. There has been limited success in the identification of clinically active agents with the ability to inhibit the function or generation of MDSC. Ibrutinib is an orally available irreversible inhibitor of Bruton's tyrosine kinase (BTK) that is FDA approved for the treatment of B cell malignancies. In addition to B cells, cells of the myeloid lineage including monocytes and macrophages express BTK, and treatment with ibrutinib has been shown to alter their function and differentiation. As a result, it was hypothesized that ibrutinib would interfere with the function or generation of MDSC in the setting of cancer. MDSC isolated from the spleens of multiple murine tumor models (EMT6, 4T1, and C26) as well as MDSC from patients with metastatic melanoma expressed BTK. Treatment with ibrutinib at doses ranging from 0.1-5 μM inhibited the phosphorylation of BTK in both murine and human MDSC. Ibrutinib treatment of murine and human MDSC resulted in a significant reduction in nitric oxide (NO) production (p&amp;lt; 0.05), but had only modest effects on MDSC levels of IDO and arginase. Ibrutinib was also able to inhibit murine MDSC migration in response to EMT6 cell line conditioned media and the chemokine CXCL12 (p&amp;lt; 0.05). In addition, ibrutinib inhibited human MDSC migration in response to GM CSF (p&amp;lt; 0.05). Ibrutinib reduced the expression of the myeloid adhesion molecules CD11a (p&amp;lt; 0.05) and CD49D (p&amp;lt; 0.01) by MDSC, which could explain the reduction in migration. Importantly, ibrutinib significantly reduced the ability of MDSC to suppress CD8+ T cell proliferation compared to DMSO (21.98% vs. 12.49% proliferation, p&amp;lt; 0.05). Daily treatment with ibrutinib effectively inhibited the in vitro generation of human MDSC from monocytes by promoting HLA DR expression (p&amp;lt; 0.05). Using the EMT6 mammary carcinoma model in vivo, ibrutinib treatment resulted in a significant reduction of MDSC in both the spleen and tumor (p&amp;lt; 0.05). Ibrutinib also reduced the frequency of splenic MDSC in wild type B16F10 tumor bearing mice, but not in BTK mutant XID mice. In addition, both murine and human MDSC did not express significant levels of alternative ibrutinib targets including ITK, Bmx, and Blk. These results suggest that inhibition of BTK is the primary driver behind the observed effects of ibrutinib on MDSC function and generation. Finally, the combination of ibrutinib and anti PDL1 therapy was significantly more effective than either agent alone (p&amp;lt; 0.01 and p&amp;lt; 0.05) producing complete tumor regression in 50% of EMT6 tumor being mice. The results support further investigation of ibrutinib in combination with immune based therapies for solid tumors. Citation Format: Andrew R. Stiff, Prashant Trikha, Robert Wesolowski, Kari Kendra, Sarvani Uppati, David Abood, Elizabeth McMichael, Megan Duggan, Amanda Campbell, Natarajan Muthusamy, Susheela Tridandapani, Michael Caliguiri, John C. Byrd, William E. Carson. Ibrutinib, a BTK inhibitor, impairs the generation and function of myeloid derived suppressor cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 553.</jats:p

Abstract CT143: A phase I/II trial of cetuximab in combination with interleukin-12 administered to patients with unresectable primary or recurrent squamous cell carcinoma of the head and neck

Abstract Introduction: Preclinical investigations demonstrated that IL-12 significantly enhances the lytic actions and cytokine production of NK cells against cetuximab-coated HER1-positive SCCHN cell lines via synergistic activation of the MAP kinase pathway regardless of tumor cell HPV infection status. This phase I/II trial evaluated the combination of IL-12 with cetuximab to enhance NK cell effector mechanisms in patients with unresectable primary or recurrent squamous cell carcinoma of the head and neck. Patients/Methods: The phase I dose escalation portion of the trial included 6 patients that received 500 mg/m2 cetuximab i.v. on day 1 of a 2 week cycle with either 0.2 mcg/kg or 0.3 mcg/kg IL-12 given s.c. on days 2 and 5 of the 2 week cycle, beginning with cycle 2. The phase II portion of the trial included 17 patients that received a combination of 500 mg/m2 cetuximab i.v. plus 0.3 mcg/kg IL-12 s.c. (MTD) following the phase I schema. Correlative immune studies using patient blood and plasma obtained prior to and during therapy included measurement of antibody-dependent cytotoxicity (ADCC), serum cytokine analysis, determination of NK cell FcγRIIIa polymorphisms, and myeloid derived suppressor cell (MDSC) frequency. Results: 23 patients with unresectable primary or recurrent SCCHN were accrued (22 male, 1 female, avg. age 60.2 yrs). The combination therapy was well tolerated. Grade 4 AST and ALT increase was the only adverse event reported in the phase I portion which accrued 6 patients. The MTD was determined to be 0.3 mcg/kg s.c. 15 patients achieved stable disease for an average of 35 weeks (range 6-87). 60% of patients showed heightened ADCC from a baseline reading by the end of cycle 4, averaging an increase of 8.6% lysis. but there was not correlation with overall survival. Patients with progression-free survival (PFS) greater than 100 days showed an increased secretion of IFNγ, IP-10, MIP-1α, and TNF-α in sera from baseline to end of cycle 5, increasing by 81.7%, 53.3%, and 29.6% respectively. 6 patients carried the VV high affinity NK cell FcγRIIIa polymorphism, and PBMCs from these patients were able to better lyse cetuximab-coated SCCHN tumor cells compared to 10 patients with the FF low affinity receptor (25.7% lysis compared to 5.4% lysis at the 25:1 E:T ratio). MDSCs comprised an average of 5.3% of circulating cells. An analysis of MDSC incidence revealed that 15 of 23 majority of patients had a greater percentage of the monocytic subset of MDSCs versus the granulocytic MDSC subset, and these patients achieved an average of 28 weeks of progression free survival (PFS), compared to 13 week PFS in patients with a higher granulocytic MDSC population. Conclusions: These findings suggest that the addition of IL-12 to cetuximab may lead to enhanced efficacy through the induction of anti-tumor immunity. Citation Format: Elizabeth McMichael, Amanda Campbell, Megan Duggan, Tiffany Noel, Melanie Davis, Kallan Opheim, Kala Levine, Lakhvir Atwal, Gonzalo Olaverria Salavaggione, Akansha Gansu, Sarvani Uppati, Bonnie Paul, Thomas Olencki, Theodoros Teknos, Panayiotis Savvides, Stephen Liu, William Carson. A phase I/II trial of cetuximab in combination with interleukin-12 administered to patients with unresectable primary or recurrent squamous cell carcinoma of the head and neck. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT143.</jats:p