The role of the immune system in brain metastasis

Metastatic brain tumors are the most common brain tumors in adults. With numerous successful advancements in systemic treatment of most common cancer types, brain metastasis is becoming increasingly important in the overall prognosis of cancer patients. Brain metastasis of peripheral tumor is the result of complex interplay of primary tumor, immune system and central nervous system microenvironment. Once formed, brain metastases hide behind the blood brain barrier and become inaccessible to chemotherapies that are otherwise successful in targeting systemic cancer. The approval of immune checkpoint inhibitors for several common cancers such as advanced melanoma and lung cancers brings with it the opportunity and obligation to further understand the mechanisms of immunosuppression by tumors that spread to the brain as well as the interaction between the brain environment and tumor microenvironment. In this review paper we define the central role of the immune system in the development of brain metastases. We performed a comprehensive review of the literature to outline the molecular mechanisms of immunosuppression used by tumors and how the immune system interacts with the central nervous system to facilitate brain metastasis. In particular we discuss the tumor-type-specific mechanisms of metastasis of cancers that preferentially metastasize to the brain as well as the therapies that effectively modulate the immune response, such as immune checkpoint inhibitors and vaccines

CELL-SPECIFIC INTERLEUKIN-10 EXPRESSION IN THE GASTROINTESTINAL TRACT AND ITS IMPACT ON A MODEL OF ACUTE COLITIS

Inflammatory Bowel Diseases (IBDs) are chronic diseases characterized by aberrant inflammation in the gastrointestinal tract. They result in a significant reduction in the quality of life for 1.3 million Americans every year, and are implicated in more severe pathologies like colorectal cancer. While knowledge of the gastrointestinal immune system has vastly improved recently, the etiology of IBDs like Crohn’s disease and ulcerative colitis remain largely unknown. What is known, though, is that the maintenance of the epithelial layer and immunoregulatory mechanisms are pivotal toward the treatment and prevention of these diseases. Interleukin-10 (IL-10) plays an important role in immunoregulation and the induction of tolerance in the gastrointestinal tract, and has been previously shown by our lab to be constitutively expressed in intestinal epithelial cells. In order to elucidate the role of this epithelial-derived IL-10 in gastrointestinal health and the development of IBD a two prong approach was taken. First, an examination of how certain microbial species in the gastrointestinal tract affect IL-10 expression was performed. Then, an examination of how IL-10 signaling in intestinal epithelial cells affects the disease phenotype in a model of acute colitis was performed. It was found that the presence of bacteria in the gastrointestinal tract was important for the expression of IL-10 in both the lamina propria and epithelial layer, but the results were unable to determine whether certain species are more inclined to induce this expression than others. It was also observed that mice with impaired IL-10 signaling in their intestinal epithelial cells exhibited a less severe acute colitis phenotype when treated with dextran sulfate sodium

Children's Perception of Speech Produced in a Two-Talker Background

This study evaluated the degree to which children benefit from the acoustic modifications made by talkers when they produce speech in noise

Achieving Value in Spine Surgery: 10 Major Cost Contributors.

STUDY DESIGN: Narrative Review. OBJECTIVES: The increasing cost of healthcare overall and for spine surgery, coupled with the growing burden of spine-related disease and rising demand have necessitated a shift in practice standards with a new emphasis on value-based care. Despite multiple attempts to reconcile the discrepancy between national recommendations for appropriate use and the patterns of use employed in clinical practice, resources continue to be overused-often in the absence of any demonstrable clinical benefit. The following discussion illustrates 10 areas for further research and quality improvement. METHODS: We present a narrative review of the literature regarding 10 features in spine surgery which are characterized by substantial disproportionate costs and minimal-if any-clear benefit. Discussion items were generated from a service-wide poll; topics mentioned with great frequency or emphasis were considered. Items are not listed in hierarchical order, nor is the list comprehensive. RESULTS: We describe the cost and clinical data for the following 10 items: Over-referral, Over-imaging & Overdiagnosis; Advanced Imaging for Low Back Pain; Advanced imaging for C-Spine Clearance; Advanced Imaging for Other Spinal Trauma; Neuromonitoring for Cervical Spine; Neuromonitoring for Lumbar Spine/Single-Level Surgery; Bracing & Spinal Orthotics; Biologics; Robotic Assistance; Unnecessary perioperative testing. CONCLUSIONS: In the pursuit of value in spine surgery we must define what quality is, and what costs we are willing to pay for each theoretical unit of quality. We illustrate 10 areas for future research and quality improvement initiatives, which are at present overpriced and underbeneficial

Bundled Payment Models in Spine Surgery.

STUDY DESIGN: The following is a narrative discussion of bundled payments in spine surgery. OBJECTIVE: The cost of healthcare in the United States has continued to increase. To lower the cost of healthcare, reimbursement models are being investigated as potential cost saving interventions by driving incentives and quality improvement in fields such a spine surgery. METHODS: Narrative overview of literature pertaining to bundled payments in spine surgery synthesizing findings from computerized databases and authoritative texts. RESULTS: Spine surgery is challenging to define payment modes because of high cost variability and surgical decision-making nuances. While implementing bundled care payments in spine surgery, it is important to understand concepts such as value-based purchasing, episodes of care, prospective versus retrospective payment models, one versus two-sided risk, risk adjustment, and outlier protection. Strategies for implementation underscore the importance of risk stratification and modeling, adoption of evidence based clinical pathways, and data collection and dissemination. While bundled care models have been successfully implemented, challenges facing institutions adopting bundled care payment models include financial stressors during adoption of the model, distribution of risks, incentivization of treating only low risk patients, and nuanced variation in procedures leading to variation in costs. CONCLUSION: An alternative for fee for service payments, bundled care payments may lead to higher cost savings and surgeon accountability in a patient\u27s care

Less in-toeing after femoral derotation osteotomy in adult patients with increased femoral version and posterior hip impingement compared to patients with femoral retroversion

In-toeing of the foot was associated with high femoral version (FV), while Out-toeing was associated with femoral-retroversion. Therefore, we report on (i) foot-progression-angle (FPA), (ii) prevalence of In-toeing and Out-toeing, and (iii) clinical outcome of patients treated with femoral-derotation-osteotomy (FDO). We performed a retrospective analysis involving 20 patients (20 hips) treated with unilateral FDO (2017-18). Of them, 14 patients had increased FV, 6 patients had femoral-retroversion. Follow-up time was mean 1 ± 1 years. All patients had minimal 1-year follow-up and the mean age was 29 ± 8 years. Patients with increased FV (FV > 35°) presented with positive posterior-impingement-test and mean FV was 49 ± 11° (Murphy method). Six patients with femoral-retroversion (FV < 10°) had positive anterior impingement test and mean FV of 5 ± 4°. Instrumented gait analysis was performed preoperatively and at follow-up using the Gaitrite system to measure FPA and was compared to a control group of 18 healthy asymptomatic volunteers (36 feet, mean age 29 ± 6 years). (i) Mean FPA increased significantly (P = 0.006) from preoperative 1.3 ± 7° to 4.5 ± 6° at follow-up for patients with increased FV and was not significantly different compared to the control group (4.0 ± 4.5°). (ii) In-toeing decreased from preoperatively (five patients) to follow-up (two patients) for patients with increased FV. Out-toeing decreased from preoperatively (two patients) to follow-up (no patient) for patients with femoral-retroversion. (iii) Subjective-hip-value of all patients increased significantly (P < 0.001) from preoperative 21 to 78 points at follow-up. WOMAC was 12 ± 8 points at follow-up. Patients with increased FV that underwent FDO walked with less In-toeing. FDO has the potential to reduce In-toeing and Out-toeing and to improve subjective satisfaction at follow-up

Minimal Out-Toeing and Good Hip Scores of Severe SCFE Patients Treated With Modified Dunn Procedure and Contralateral Prophylactic Pinning at Minimal 5-year Follow up

Background: Slipped capital femoral epiphyses (SCFE) is associated with out-toeing of the foot and external rotation gait. But it is unknown if SCFE patients treated with the modified Dunn procedure have out-toeing at follow up.Therefore, we used instrumented gait analysis and questioned (1) do severe SCFE patients treated with a modified Dunn procedure have symmetrical foot progression angle (FPA) compared with contralateral side and compared with asymptomatic volunteers (2) what is the prevalence of out-toeing gait and what are the outcome socres at follow up. Methods: Gait analysis of 22 patients (22 hips) treated with an unilateral modified Dunn procedure for severe SCFE (slip angle >60 degrees, 2002 to 2011) was retrospectively evaluated. Of 38 patients with minimal 5-year follow up, 2 hips (4%) had avascular necrosis of the femoral head and were excluded for gait analysis. Twenty-two patients were available for gait analysis at follow up (mean follow up of 9±2 y). Mean age at follow up was 22±3 years. Mean preoperative slip angle was 64±8 degrees (33% unstable slips) and decreased postoperatively (slip angle of 8±4 degrees). Gait analysis was performed with computer-based instrumented walkway system (GAITRite) to measure FPA with embedded pressure sensors. Patients were compared with control group of 18 healthy asymptomatic volunteers (36 feet, mean age 29±6 y). Results: (1) Mean FPA of SCFE patients (3.6±6.4 degrees) at follow up was not significantly different compared with their contralateral side (5.6±5.5 degrees) and compared with FPA of controls (4.0±4.5 degrees). (2) Of the 22 SCFE patients, most of them (19 hips, 86%) had normal FPA (-5 to 15 degrees), 2 patients had in-toeing (FPA15 degrees) and was not significantly different compared with control group. (3) Mean modified Harris hip score (mHHS) was 93±11 points, mean Hip Disability and Osteoarthritis Outcome Score (HOOS) score was 91±10 points. Three patients (14%) had mHHS 95 points. Conclusions: Patients with severe SCFE treated with modified Dunn procedure had mostly symmetrical FPA and good hip scores at long term follow up. This is in contrast to previous studies. Although 1 patient had out-toeing and 2 patients had in-toeing at follow up, they had good hip scores. Level of evidence: Level III-retrospective comparative study

Genome wide DNA methylation landscape reveals glioblastoma’s influence on epigenetic changes in tumor infiltrating CD4+ T cells

CD4+ helper T (Th) cells play a critical role in shaping anti-tumor immunity by virtue of their ability to differentiate into multiple lineages in response to environmental cues. Various CD4+ lineages can orchestrate a broad range of effector activities during the initiation, expansion, and memory phase of endogenous anti-tumor immune response. In this clinical corelative study, we found that Glioblastoma (GBM) induces multi- and mixed-lineage immune response in the tumor microenvironment. Whole-genome bisulfite sequencing of tumor infiltrating and blood CD4+ T-cell from GBM patients showed 13571 differentially methylated regions and a distinct methylation pattern of methylation of tumor infiltrating CD4+ T-cells with significant inter-patient variability. The methylation changes also resulted in transcriptomic changes with 341 differentially expressed genes in CD4+ tumor infiltrating T-cells compared to blood. Analysis of specific genes involved in CD4+ differentiation and function revealed differential methylation status of TBX21, GATA3, RORC, FOXP3, IL10 and IFNG in tumor CD4+ T-cells. Analysis of lineage specific genes revealed differential methylation and gene expression in tumor CD4+ T-cells. Interestingly, we observed dysregulation of several ligands of T cell function genes in GBM tissue corresponding to the T-cell receptors that were dysregulated in tumor infiltrating CD4+ T-cells. Our results suggest that GBM might induce epigenetic alterations in tumor infiltrating CD4+ T-cells there by influencing anti-tumor immune response by manipulating differentiation and function of tumor infiltrating CD4+ T-cells. Thus, further research is warranted to understand the role of tumor induced epigenetic modification of tumor infiltrating T-cells to develop effective anti-GBM immunotherapy

Soft-bound synaptic plasticity increases storage capacity

Accurate models of synaptic plasticity are essential to understand the adaptive properties of the nervous system and for realistic models of learning and memory. Experiments have shown that synaptic plasticity depends not only on pre- and post-synaptic activity patterns, but also on the strength of the connection itself. Namely, weaker synapses are more easily strengthened than already strong ones. This so called soft-bound plasticity automatically constrains the synaptic strengths. It is known that this has important consequences for the dynamics of plasticity and the synaptic weight distribution, but its impact on information storage is unknown. In this modeling study we introduce an information theoretic framework to analyse memory storage in an online learning setting. We show that soft-bound plasticity increases a variety of performance criteria by about 18% over hard-bound plasticity, and likely maximizes the storage capacity of synapses