Epigenetic Therapy Ties MYC Depletion to Reversing Immune Evasion and Treating Lung Cancer.

Combining DNA-demethylating agents (DNA methyltransferase inhibitors [DNMTis]) with histone deacetylase inhibitors (HDACis) holds promise for enhancing cancer immune therapy. Herein, pharmacologic and isoform specificity of HDACis are investigated to guide their addition to a DNMTi, thus devising a new, low-dose, sequential regimen that imparts a robust anti-tumor effect for non-small-cell lung cancer (NSCLC). Using in-vitro-treated NSCLC cell lines, we elucidate an interferon α/ß-based transcriptional program with accompanying upregulation of antigen presentation machinery, mediated in part through double-stranded RNA (dsRNA) induction. This is accompanied by suppression of MYC signaling and an increase in the T cell chemoattractant CCL5. Use of this combination treatment schema in mouse models of NSCLC reverses tumor immune evasion and modulates T cell exhaustion state towards memory and effector T cell phenotypes. Key correlative science metrics emerge for an upcoming clinical trial, testing enhancement of immune checkpoint therapy for NSCLC.

Impact of Postoperative COVID-19 Infection Status on Outcomes in Elective Primary Total Joint Arthroplasty.

BACKGROUND: Although Coronavirus disease 2019 (COVID-19) infection causes major morbidity and mortality, it is unclear what the impact of postoperative COVID-19 infection is on 30-day outcomes after total joint arthroplasty (TJA). METHODS: There were 2,340 patients who underwent TJA in 2021, identified using the National Surgical Quality Improvement Program database, with 925 total hip arthroplasty (THA) patients (39.5%) and 1,415 total knee arthroplasty (TKA) patients (60.5%), overall. Propensity score matching was implemented using patient demographics and preoperative medical conditions to compare outcomes for postoperative COVID-19-positive and COVID-19-negative patients who underwent TKA or THA. RESULTS: Postoperative COVID-19-positive THA patients were found to have a significantly increased risk of pneumonia (odds ratio [OR] 42.57), sepsis (OR 12.77), readmission (OR 12.06), non-home discharge (OR 3.78), and longer length of stay (hazard ratio 1.62). Postoperative COVID-19-positive TKA patients had an increased risk of 30-day mortality (OR 14.17), superficial infection (OR 3.17), pneumonia (OR 34.68), unplanned intubation (OR 18.31), ventilator use for more than 48 hours (OR 18.31), pulmonary embolism (OR 11.98), urinary tract infection (OR 5.16), myocardial infarction (OR 16.02), deep vein thrombosis (OR 4.69), non-home discharge (OR 1.79), reoperation (OR 3.17), readmission (OR 9.61), and longer length of stay (hazard ratio 1.49). CONCLUSIONS: Patients who contracted COVID-19 within 30 days after TJA were at increased risk of mortalities, medical complications, readmissions, reoperations, and non-home discharges. It is important for orthopedic surgeons to understand these adverse outcomes to better counsel patients and mitigate these risks, particularly in higher risk populations.

Comparing Pain and Pain Coping Mechanisms in Patients Undergoing Total Joint Arthroplasty as Part of a Mission Trip to Those in the United States.

BACKGROUND: Access to total joint arthroplasty can be difficult in low-resource settings. Service trips are conducted to provide arthroplasty care to populations in need around the world. This study aimed to compare the pain, function, surgical expectations, and coping mechanisms of patients from one such service trip to the United States. METHODS: In 2019, the Operation Walk program conducted a service trip in Guyana during which 50 patients had hip or knee arthroplasties. Patient demographics, patient-reported outcome measures, questionnaires assessing pain attitudes and coping, and pain visual analog scales were collected preoperatively and at 3 months postoperatively. These outcomes were compared with a matched cohort of elective total joint arthroplasty at a US tertiary care medical center. There were 37 patients matched between the 2 cohorts. RESULTS: The mission cohort had significantly lower preoperative self-reported function scores than the US cohort (38.3 versus 47.5, P = .003), as well as a significantly larger improvement at 3 months (42.4 versus 26.4, P = .014). The mission cohort had significantly higher initial pain (8.0 versus 7.0, P = .015), but there were no differences with regard to pain at 3 months (P = .420) or change in pain (P = .175). The mission cohort had significantly greater preoperative scores in pain attitude and coping responses. CONCLUSION: Patients in low-resource settings were more likely to have preoperative functional limitations and pain, and they coped with pain through prayer. Understanding the key differences between these 2 types of populations and how they approach pain and functional limitations may help improve care for each group. LEVEL OF EVIDENCE: II, prospective study.

Ultracongruent Designs Compared to Posterior-Stabilized and Cruciate-Retaining Tibial Inserts - What Does the Evidence Tell Us? A Systematic Review and Meta-Analysis.

BACKGROUND: Posterior-stabilized (PS) and cruciate-retaining (CR) have been the most common tibial designs used in total knee arthroplasty. Ultra-congruent (UC) inserts are becoming popular because they preserve bone without relying on the posterior cruciate ligament balance and integrity. Despite increasing use, there is no consensus on how UC inserts perform versus PS and CR designs. METHODS: A comprehensive literature search of 5 online databases was performed for articles from January 2000 to July 2022 comparing the kinematic and clinical outcomes of PS or CR tibial inserts to UC inserts. There were nineteen studies included. There were 5 studies comparing UC to CR and 14 comparing UC to PS. Only one randomized controlled trial (RCT) was rated "good quality". RESULTS: For CR studies, pooled analyses showed no difference in knee flexion (n = 3, P = .33) or Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores (n = 2, P = .58). For PS studies, meta-analyses showed better anteroposterior stability (n = 4, P < .001) and more femoral rollback (n = 2, P < .001) for PS but no difference in knee flexion (n = 9, P = .55) or medio-lateral stability (n = 2, P = .50). There was no difference with WOMAC (n = 5, P = .26), Knee Society Score (n = 3, P = .58), Knee Society Knee Score (n = 4, P = .76), or Knee Society Function Score (n = 5, P = .51). CONCLUSION: Available data demonstrates there are no clinical differences between CR or PS and UC inserts in small short-term studies ending around 2 years after surgery. More importantly, high-quality research comparing all inserts is lacking, demonstrating a need for more uniform and longer-term studies beyond 5 years after surgery to justify increased UC usage.

Racial, Socioeconomic, and Payer Status Disparities in Utilization of Total Ankle Arthroplasty Compared to Ankle Arthrodesis.

Total ankle arthroplasty is increasingly being used for the treatment of ankle osteoarthritis when compared to arthrodesis. However, there has been limited investigation into disparities in utilization of these comparable procedures. This study examined racial/ethnic, socioeconomic, and payer status disparities in the likelihood of undergoing total ankle arthroplasty compared with ankle arthrodesis. Patients with a diagnosis of ankle osteoarthritis from 2006 through 2019 were identified in the National Inpatient Sample, then subclassified as undergoing total ankle arthroplasty or arthrodesis. Multivariable logistic regression models, adjusted for hospital location, primary or secondary osteoarthritis diagnosis, and patient characteristics (age, sex, infection, and Elixhauser comorbidities), were used to examine the effect of race/ethnicity, socioeconomic status, and payer status on the likelihood of undergoing total ankle arthroplasty versus arthrodesis. Black and Asian patients were 34% and 41% less likely than White patients to undergo total ankle arthroplasty rather than arthrodesis (p < .001). Patients in income quartiles 3 and 4 were 22% and 32% more likely, respectively, than patients in quartile 1 to undergo total ankle arthroplasty rather than arthrodesis (p = .001 and p = .01, respectively). In patients <65 years of age, privately insured and Medicare patients were 84% and 37% more likely, respectively, than Medicaid patients to undergo total ankle arthroplasty rather than arthrodesis (p < .001). Racial/ethnic, socioeconomic, and payer status disparities exist in the likelihood of undergoing total ankle arthroplasty versus arthrodesis for ankle osteoarthritis. More work is needed to establish drivers of these disparities and identify targets for intervention, including improvements in parity in relative procedure utilization.

Fortuitous Eradication of an Aggressive Basal Cell Carcinoma Via Foreign Body Reaction to a Polyurethane Vacuum-Assisted Closure Sponge.

ABSTRACT: The foreign body reaction (FBR) is a well-documented immune reaction. Much of the literature on FBRs has focused on minimizing this immune response to mitigate the impact on medical implants. Here, we present a case that illustrates a serendipitous oncologic outcome from an FBR. A 54-year-old man presented with an aggressive basal cell carcinoma (BCC). At the first resection, he had broadly positive surgical margins. The surgical wound was temporized with a polyurethane wound vacuum assisted closure (VAC) device. He was lost to follow-up having retained a VAC sponge for a total of 12 weeks. A wide re-resection was performed 7 months after the initial resection. Exhaustive examination of the resected specimen was performed. There was an absence of any BCC, replaced by a widespread chronic FBR to polyurethane VAC sponge particles. This suggests that the foreign body immune response was sufficiently intense to eradicate any remaining BCC. This case illustrates the concept of an FBR as a novel method of local immunotherapy.

Preoperative COVID-19 infection status negatively impacts postoperative outcomes of geriatric hip fracture surgery.

OBJECTIVES: Compare outcomes for patients with recently diagnosed COVID-19 infection to those without COVID-19 infection undergoing operative treatment of hip fractures using the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database. DESIGN: Retrospective propensity score matched cohort. METHODS: Patients who received surgery for an acute hip fracture (intramedullary nail (IMN), open reduction internal fixation (ORIF) or hemiarthroplasty) in 2021 were identified from the NSQIP database. Propensity score matching was implemented using patient demographics and preoperative medical conditions to compare outcomes for COVID-19-positive and COVID-19-negative cohorts. RESULTS: After matching, COVID-19-positive patients exhibited a higher risk of 30-day mortality (Odds ratio (OR) 1.48, 95 % confidence interval (CI) 1.01 - 2.04), pneumonia (OR 2.90, 95 % CI: 1.91 - 4.33), unplanned intubation (OR 2.53, 95 % CI: 1.39 - 4.39), and septic shock (OR 2.51, 95 % CI: 1.10 - 4.67). COVID-19-positive patients were also more likely to have a longer length of hospital stay (Hazard Ratio 1.3, 95 % CI: 1.20 - 1.41) and were more likely to be discharged to an acute care hospital (OR 1.90, 95 % CI: 1.03 - 3.06). CONCLUSIONS: Active COVID-19 infection is an independent risk factor for complications as well as increased resource utilization in patients undergoing surgical treatment of acute hip fracture. Using the results of this multicenter study, quantification of these risks can help inform practice and treatment protocols for this population. LEVEL OF EVIDENCE: III.

Intraosseous Tibial Resuscitation After a Total Knee Arthroplasty Leading to Osteonecrosis and Loosening of the Tibial Component.

A 51-year-old woman suffered cardiac arrest requiring emergent intraosseous access that abutted the tibial component of her total knee arthroplasty. She developed a wound at the site and knee pain which was concerning for deep infection. Subsequent imaging was consistent with osteonecrosis developing around the tibial component. The component eventually loosened, requiring a revision surgery. Her deep cultures remained negative throughout. Her findings are most consistent with osteonecrosis and aseptic loosening of her prosthesis. While intraosseous access may be beneficial during resuscitation, it has complications. This is the first reported case of osteonecrosis secondary to intraosseous access leading to prosthetic loosening necessitating a revision surgery.

Racial and Socioeconomic Disparities in Risk and Reason for Revision in Total Joint Arthroplasty.

INTRODUCTION: Data regarding racial/ethnic and socioeconomic differences in revision total hip arthroplasty (rTHA) and revision total knee arthroplasty (rTKA) have been inconsistent. This study examined racial/ethnic and socioeconomic disparities in comorbidity-adjusted risk and reason for rTHA and rTKA. METHODS: Patients who underwent rTHA or rTKA between 2006 and 2014 in the National Inpatient Sample were identified. Multivariable logistic regression models adjusted for payer status, hospital geographic setting, and patient characteristics (age, sex, and Elixhauser Comorbidity Index) were used to examine the effect of race/ethnicity and socioeconomic status on trends in annual risk of rTHA/rTKA and causes of rTHA/rTKA. RESULTS: Black patients were less likely to undergo rTHA and more likely to undergo rTKA while Hispanic patients were more likely to undergo rTHA and less likely to undergo rTKA ( P < 0.001 for all) compared with White patients. Patients residing in areas of lower income quartiles were more likely to undergo rTHA and rTKA compared with those in the highest quartile ( P < 0.001), and these disparities persisted and widened over time. Black, Hispanic, and Asian patients were less likely to undergo rTHA/rTKA because of dislocation compared with White patients ( P < 0.001 for all). Patients from areas of lower income quartiles were more likely to undergo rTHA because of septic complications and less likely to require both rTHA and rTKA because of mechanical complications ( P < 0.001 for all). DISCUSSION: Racial/ethnic and socioeconomic disparities exist in risk and cause of rTHA and rTKA. Increasing awareness and a focus on minimizing variability in hospital quality may help mitigate these disparities.

Mapping the course to recovery: a prospective study on the anatomic distribution of early postoperative pain after total knee arthroplasty.

INTRODUCTION: Early postoperative pain following total knee arthroplasty significantly impacts outcomes and patient satisfaction. However, the characteristics and sources of early pain after total knee arthroplasty remain unclear. Therefore, the purpose of this study was to determine the anatomic distribution and course of postoperative pain in the acute and subacute period following total knee arthroplasty. METHODS: A prospective observational study of primary, elective unilateral total knee arthroplasty cases was conducted at our academic tertiary care medical center from January 2021 to September 2021. Preoperative variables were extracted from institutional electronic medical records. Postoperatively, patients utilized a knee pain map to identify the two locations with the most significant pain and rated it using the visual analog scale (VAS). The data were collected on day 0, at 2 weeks, 2 months, and 6 months after operation. RESULTS: This study included 112 patients, with 6% of patients having no pain at postoperative day 0, 22% at 2 weeks, 46% at 2 months, and 86% at 6 months after operation. In those who reported pain, the VAS score (mean ± standard deviation) was 5.8 ± 2.4 on postoperative day 0 and decreased at each follow-up time point (5.4 ± 2.3 at 2 weeks, 3.9 ± 2.2 at 2 months, and 3.8 ± 2.7 at 6 months). The majority of patients were able to identify distinct loci of pain. The most common early pain loci were patellae, thigh, and medial joint line, and this distribution dissipated by 6 months. CONCLUSION: At 2 postoperative weeks, pain was primarily at the medial joint, and at 6 months postoperatively, pain was more likely to be at the lateral joint. No relationship was found between pain at six months and pain scores or location at postoperative day 0 or 2 weeks. Understanding the distribution and progression of knee pain following total knee arthroplasty may benefit patient education and targeted interventions. LEVEL OF EVIDENCE: Level II, prospective observational study.

Distinguishing Pseudosubluxation From True Injury: A Case of C2-3 and C3-4 Subluxation in a Pediatric Patient.

A 6-year-old girl presented with a one-week history of neck pain after a trampoline accident. Cervical radiographs interpreted as pseudosubluxation of C2 on C3. CT demonstrated the reversal of lordosis with anterolisthesis of C2-C3 and C3-C4. Ten weeks after two months of halo traction, radiographs demonstrated anatomic alignment and maintained disk heights. This case highlights the similarities of pseudosubluxation and true injury, emphasizing the need for high index of suspicion in this population and a successful treatment of subluxation using a halo construct.

Bacterial-Driven Inflammation and Mutant BRAF Expression Combine to Promote Murine Colon Tumorigenesis That Is Sensitive to Immune Checkpoint Therapy.

Colorectal cancer is multifaceted, with subtypes defined by genetic, histologic, and immunologic features that are potentially influenced by inflammation, mutagens, and/or microbiota. Colorectal cancers with activating mutations in BRAF are associated with distinct clinical characteristics, although the pathogenesis is not well understood. The Wnt-driven multiple intestinal neoplasia (MinApcΔ716/+) enterotoxigenic Bacteroides fragilis (ETBF) murine model is characterized by IL17-dependent, distal colon adenomas. Herein, we report that the addition of the BRAF V600E mutation to this model results in the emergence of a distinct locus of midcolon tumors. In ETBF-colonized BRAF V600E Lgr5 CreMin (BLM) mice, tumors have similarities to human BRAF V600E tumors, including histology, CpG island DNA hypermethylation, and immune signatures. In comparison to Min ETBF tumors, BLM ETBF tumors are infiltrated by CD8+ T cells, express IFNγ signatures, and are sensitive to anti-PD-L1 treatment. These results provide direct evidence for critical roles of host genetic and microbiota interactions in colorectal cancer pathogenesis and sensitivity to immunotherapy. SIGNIFICANCE: Colorectal cancers with BRAF mutations have distinct characteristics. We present evidence of specific colorectal cancer gene-microbial interactions in which colonization with toxigenic bacteria drives tumorigenesis in BRAF V600E Lgr5 CreMin mice, wherein tumors phenocopy aspects of human BRAF-mutated tumors and have a distinct IFNγ-dominant immune microenvironment uniquely responsive to immune checkpoint blockade.This article is highlighted in the In This Issue feature, p. 1601.

McArdle Disease vs. Stiff-Person Syndrome: A Case Report Highlighting the Similarities Between Two Rare and Distinct Disorders.

McArdle disease is a rare autosomal recessive disorder of muscle glycogen metabolism that presents with pain and fatigue during exercise. Stiff-Person Syndrome is an autoimmune-related neurologic process characterized by fluctuating muscle rigidity and spasm. Reported is a 41-year-old male who presented to the emergency department due to sudden-onset weakness and chest pain while moving his refrigerator at home. Cardiac workup was non-contributory, but a creatine kinase level > 6,000 warranted a muscle biopsy. The biopsy pathology report was misinterpreted to be diagnostic for McArdle disease given the clinical presentation. After 4 years of treatment without symptomatic improvement, a gradual transition of symptoms from pain alone to pain with stiffness was noted. A positive glutamic acid decarboxylase antibody test resulted in a change of diagnosis to Stiff-Person Syndrome. This is the first known case that highlights the similarities between these two rare and distinct disease processes, highlighting the necessity for thorough history taking, maintenance of a broad differential diagnosis, and knowledge of how best to interpret complex pathology reports.