Jason B. Anari

Loss of interferon regulatory factor 5 (IRF5) expression in human ductal carcinoma correlates with disease stage and contributes to metastasis

IntroductionNew signaling pathways of the interleukin (IL) family, interferons (IFN) and interferon regulatory factors (IRF) have recently been found within tumor microenvironments and in metastatic sites. Some of these cytokines stimulate while others inhibit breast cancer proliferation and/or invasion. IRFs, a family of nine mammalian transcription factors, have multiple biologic functions that when dysregulated may contribute to tumorigenesis; most well-known are their roles in regulating/initiating host immunity. Some IRF family members have been implicated in tumorigenesis yet little is still known of their expression in primary human tumors or their role(s) in disease development/progression. IRF5 is one of the newer family members to be studied and has been shown to be a critical mediator of host immunity and the cellular response to DNA damage. Here, we examined the expression of IRF5 in primary breast tissue and determined how loss of expression may contribute to breast cancer development and/or progression.MethodsFormalin-fixed paraffin-embedded archival breast tissue specimens from patients with atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) were examined for their expression of IRF1 and IRF5. Knockdown or overexpression of IRF5 in MCF-10A, MCF-7 and MDA-MB-231 mammary epithelial cell lines was used to examine the role of IRF5 in growth inhibition, invasion and tumorigenesis.ResultsAnalysis of IRF expression in human breast tissues revealed the unique down-regulation of IRF5 in patients with different grades of DCIS and IDC as compared to IRF1; loss of IRF5 preceded that of IRF1 and correlated with increased invasiveness. Overexpression of IRF5 in breast cancer cells inhibited in vitro and in vivo cell growth and sensitized them to DNA damage. Complementary experiments with IRF5 siRNAs made normal mammary epithelial cells resistant to DNA damage. By 3-D culture, IRF5 overexpression reverted MDA-MB-231 to normal acini-like structures; cells overexpressing IRF5 had decreased CXCR4 expression and were insensitive to SDF-1/CXCL12-induced migration. These findings were confirmed by CXCR4 promoter reporter assays.ConclusionsIRF5 is an important tumor suppressor that regulates multiple cellular processes involved in the conversion of normal mammary epithelial cells to tumor epithelial cells with metastatic potential.

Culture-independent pilot study of microbiota colonizing open fractures and association with severity, mechanism, location, and complication from presentation to early outpatient follow-up

Precise identification of bacteria associated with post‐injury infection, co‐morbidities, and outcomes could have a tremendous impact in the management and treatment of open fractures. We characterized microbiota colonizing open fractures using culture‐independent, high‐throughput DNA sequencing of bacterial 16S ribosomal RNA genes, and analyzed those communities with respect to injury mechanism, severity, anatomical site, and infectious complications. Thirty subjects presenting to the Hospital of the University of Pennsylvania for acute care of open fractures were enrolled in a prospective cohort study. Microbiota was collected from wound center and adjacent skin upon presentation to the emergency department, intraoperatively, and at two outpatient follow‐up visits at approximately 25 and 50 days following initial presentation. Bacterial community composition and diversity colonizing open fracture wounds became increasingly similar to adjacent skin microbiota with healing. Mechanism of injury, severity, complication, and location were all associated with various aspects of microbiota diversity and composition. The results of this pilot study demonstrate the diversity and dynamism of the open fracture microbiota, and their relationship to clinical variables. Validation of these preliminary findings in larger cohorts may lead to the identification of microbiome‐based biomarkers of complication risk and/or to aid in management and treatment of open fractures.

Neuromuscular scoliosis and pelvic fixation in 2015: Where do we stand?

Neuromuscular scoliosis is a challenging problem to treat in a heterogeneous patient population. When the decision is made for surgery the surgeon must select a technique employed to correct the curve and achieve the goals of surgery, namely a straight spine over a level pelvis. Pre-operatively the surgeon must ask if pelvic fixation is worth the extra complications and infection risk it introduces to an already compromised host. Since the advent of posterior spinal fusion the technology used for instrumentation has changed drastically. However, many of the common problems seen with the unit rod decades ago we are still dealing with today with pedicle screw technology. Screw cut out, pseudoarthrosis, non-union, prominent hardware, wound complications, and infection are all possible complications when extending a spinal fusion construct to the pelvis in a neuromuscular scoliosis patient. Additionally, placing pelvic fixation in a neuromuscular patient results in extra blood loss, greater surgical time, more extensive dissection with creation of a deep dead space, and an incision that extends close to the rectum in patients who are commonly incontinent. Balancing the risk of placing pelvic fixation when the benefit, some may argue, is limited in non-ambulating patients is difficult when the literature is so mottled. Despite frequent advancements in technology issues with neuromuscular scoliosis remain the same and in the next 10 years we must do what we can to make safe neuromuscular spine surgery a reality.

Pediatric T-condylar humerus fractures: a systematic review

Background: The pediatric T-condylar humerus fracture is different from its adult counterpart, and its rarity makes general consensus for treatment algorithms difficult to define. Pediatric orthopaedic surgeons tend to think of this fracture as a supracondylar humerus fracture with intra-articular extension. The transition age at which this injury resembles the adult distal humerus fracture and less so the pediatric supracondylar humerus fracture with intra-articular extension is unclear. The goal of this study is to synthesize the literature and identify factors associated with good and poor outcomes of these problematic injuries in children and adolescents. Methods: We searched EMBASE, COCHRANE, and Medline computerized literature databases from the earliest date available in the database to 2014 using the following search term including variants and pleural counterparts: pediatric T-condylar humerus fracture. A final database of individual patients was assembled from the literature. Outcomes were rated using the method described by Jarvis and colleagues. Where possible the Arbeitsgemeinschaft für Osteosynthesefragen/Orthopaedic Trauma Association classification was used to stratify outcomes. Univariate and multivariate statistical tests were applied to the assembled database to assess differences in outcomes. Results: Patients with a triceps-splitting approach had improved Jarvis outcome scores compared with the other operative approaches as well as the best arc of motion at follow-up. In addition, 6/25 triceps split patients were 10 years old or younger compared with 3/38 Bryan-Morrey patients and 0/23 osteotomy patients. No patients with Arbeitsgemeinschaft für Osteosynthesefragen/Orthopaedic Trauma Association C3 fractures were treated with a triceps-splitting approach. When an articular approach was used, the Morrey Slide led to similar range of motion and functional outcomes as an olecranon osteotomy (P=0.616). However, the olecranon osteotomy resulted in more approach-related complications (P<0.001). An approach-related complication was associated with a poor outcome in 42% of cases. Conclusions: Pediatric T-condylar humerus fractures requiring an open approach may benefit from less invasive approaches such as the triceps split approach where the fracture pattern allows. Younger children are more amenable to less invasive means of fracture reduction and fixation. If an articular reduction is required, the aggregated literature suggests that the Morrey slide offers equivalent results to the olecranon osteotomy but with fewer approach-related complications. An olecranon osteotomy can be considered in cases of articular comminution. Level of Evidence: Level IV—therapeutic.

Tibial component considerations in bicruciate-retaining total knee arthroplasty: A 3D MRI evaluation of proximal tibial anatomy

BACKGROUND Restoration of normal anatomy and proper ligament balance are theoretical prerequisites for reproducing physiological kinematics with bicruciate-retaining total knee arthroplasty (TKA). The purpose of this study was to use a 3D MRI technique to evaluate the topography of the proximal tibia and outline considerations in tibial component design for bicruciate-retaining TKA. METHODS We identified 100 consecutive patients (50 males and 50 females) between ages 20 and 40 years with knee MRIs without arthritis, dysplasia, ACL tears, or prior knee surgery. A novel 3D MRI protocol coordinating axial, coronal, and sagittal images was used to measure: 1) medial and lateral posterior tibial slopes; 2) medial and lateral coronal slopes; and 3) distance from the anterior tibia to the ACL footprint. RESULTS There was no overall difference in medial and lateral posterior tibial slopes (5.5° (95% CI 5.0 to 6.0°) vs. 5.4° (95% CI 4.8 to 6.0°), respectively (p=0.80)), but 41 patients had side-to-side differences greater than 3°. The medial coronal slope was greater than the lateral coronal slope (4.6° (95% CI 4.0 to 5.1°) vs. 3.3° (95% CI 2.9 to 3.7°), respectively (p<0.0001)). Females had less clearance between the anterior tibia and ACL footprint than males (10.8mm (95% CI 10.4 to 11.2mm) vs. 13.0mm (95% CI 12.5 to 13.5mm), respectively (p<0.0001)). CONCLUSIONS Due to highly variable proximal tibial topography, a monoblock bicruciate-retaining tibial baseplate may not reproduce normal anatomy in all patients. LEVEL OF EVIDENCE Level IV - Anatomic research study.

The Utility of Digital Tomosynthesis to the Practicing Orthopaedic Trauma Surgeon: A Case Series.

Objective: To document the role of digital tomosynthesis (DTS) in the evaluation and treatment of orthopaedic trauma patients. Design: Retrospective case series. Setting: Level 1 trauma center with nonunion referral patient population. Participants: Four orthopaedic trauma patients with musculoskeletal injuries. Intervention: Three revision surgical procedures and 1 conservative treatment for patients with periprosthetic fractures or nonunions. Results: DTS successfully visualized 2 nonunions, 1 refracture, and 1 arthrodesis. Main Outcome Measure: Documented fracture or nonunion on imaging. Conclusions: DTS has the potential to be of significant value in the detection and follow-up of fractures. Level of Evidence: Diagnostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Vertebral body fracture after TLIF: a new complication

BackgroundThe transforaminal posterior approach (TLIF) procedure was first described in 1982. Current literature indicates its equality in outcomes for fusion constructs as other anterior-posterior procedures. As a procedure becomes more popular and is more frequently performed the types and number of complications that occur increase. We report on a two case series that underwent TLIF. Both patients had satisfactory postoperative imaging, but presented later with coronal plane vertebral body fractures in the caudal vertebral body of the TLIF construct. We believe the complication may be related to: (a) unrecognized fracture of the endplate during cage impaction; (b) overloading the endplates by maximizing the lordosis achieved by using the reverse jackknife position on a Jackson table; (c) underlying mineral bone disease in patients. As the TLIF procedure increases in popularity, caution should be exercised to avoid the same potential complications.PurposeTo describe a potential complication with the TLIF procedure.Study designCase report.Patient sample2.Outcome measureRevision surgery.MethodsCase series.ResultsCaudal vertebral body fracture is a potential complication after TLIF.ConclusionTLIF procedures can result in an unstable vertebral body fracture potentially necessitating revision decompression & stabilization. We recommend extra caution in patients with mineral bone disease, as technical errors can be magnified.

Intra-operative computed tomography guided navigation for pediatric pelvic instrumentation: A technique guide

Pelvic instrumentation for neuromuscular scoliosis has been part of neuromuscular scoliosis surgery since the era of the Luque Galveston construct. Unit Rod (Medtronic Sofamor-Danek, Nashville, TN) instrumentation brought with it the concept of cantilever correction by placing the implants in the pelvis and then gradually bringing the rod to the spine by sequentially tightening the sublaminar wires, with the goal of creating a level pelvis over a straight spine. More recently surgeons have utilized pedicle screw constructs in which the corrective strategies have varied. Challenges with pelvic fixation using iliac screws linked to the spinal rod have led to the development of the S2-alar-iliac technique (S2AI) in which the spinal rod connects to the pelvic screw. The screw is placed in the S2 ala, crosses the sacro-iliac joint and into the ilium through a large column of supra-acetabular bone. This column is the same area used for anterior inferior iliac spine external fixation frames used in trauma surgery. S2AI screw placement can be technically difficult and can require experienced radiology technologists to provide the appropriate views. Additionally, although the technique was originally described being placed via freehand technique with intra-operative flouroscopy, the freehand technique suffers from the anatomic anomalies present in the pelvis in neuromuscular scoliosis. As such, we prefer to place them using intra-operative navigation for all pediatric spinal deformity cases. Below in detail we report our intra-operative technique and an illustrative case example.

Distinguishing Pediatric Lyme Arthritis of the Hip from Transient Synovitis and Acute Bacterial Septic Arthritis: A Systematic Review and Meta-analysis

Objective Lyme arthritis is an increasingly recognized clinical entity that often prompts orthopaedic evaluation in pediatric patients. While Lyme arthritis is most common in the knee, the clinical presentation of Lyme arthritis of the hip can be similar to both acute bacterial septic arthritis and transient synovitis. Accurately distinguishing these clinical entities is important since the definitive treatment of each is distinct. Because there is limited literature on monoarticular Lyme arthritis of the hip, the purpose of this study was to perform a systematic review and meta-analysis of clinical and laboratory parameters associated with Lyme arthritis (LA) of the hip and compare them to septic arthritis (SA) and transient synovitis (TS). Study design A systematic review of the literature was performed using the following search terms, including the variants and plural counterparts “hip” and “Lyme arthritis.” A final database of individual patients was assembled from the published literature and direct author correspondence, when available. A previously published cohort of patients with hip transient synovitis or septic arthritis was used for comparative analysis. A comparative statistical analysis was performed to the assembled database to assess differences in laboratory and clinical variables between the three diagnoses. Results Data on 88 patients diagnosed with Lyme arthritis of the hip was collected and consolidated from the 12 articles meeting inclusion criteria. The average age of patients presenting with Lyme arthritis was 7.5 years (± 3.5 years), the mean erythrocyte sedimentation rate (ESR), and the C-reactive protein (CRP) was 41 mm/hr and 3.9 mg/L, respectively. Peripheral white blood cell (WBC) count averaged 10.6 x 109cells/L with the synovial WBC count averaging 55,888 cells/mm3. Compared to a previous cohort of patients with confirmed transient synovitis or septic arthritis, the 95% confidence interval for ESR was 21 - 33 mm/hr in those diagnosed with toxic synovitis (TS), 37 - 46 mm/hr for Lyme arthritis (LA), and 44 - 64 mm/hr for septic arthritis (SA). Synovial WBC counts (cells/mm3) 95% confidence intervals (CI) were 5,644 - 15,388 cells/mm3 for TS, 47,533 - 64,242 cells/mm3 for LA, and 105,432 - 260,214 cells/mm3 for SA. There was a statistically significant difference in the incidence of fever > 38.5oC (P < 0.001) and refusal to bear weight (P < 0.01) between SA, LA, and TS. Conclusions Monoarticular Lyme arthritis can be a cause of hip pain in certain geographic areas and has clinical and diagnostic overlap with transient synovitis and acute bacterial septic arthritis. This study consolidates the available literature and represents the largest series of patients diagnosed with Lyme arthritis of the hip to date. We propose a diagnostic algorithm that serially incorporates ESR, followed by a synovial neutrophil count, when evaluating pediatric patients with an irritable hip in Lyme endemic areas.

Ipsilateral femur and tibia fractures in pediatric patients: A systematic review

AIM To better understand how pediatric floating knee injuries are managed after the wide spread use of new orthopaedic technology. METHODS We searched EMBASE, COCHRANE and MEDLINE computerized literature databases from the earliest date available in the databases to February 2017 using the following search term including variants and pleural counterparts: Pediatric floating knee. All studies were thoroughly reviewed by multiple authors. Reference lists from all articles were scrutinized to identify any additional studies of interest. A final database of individual patients was assembled from the literature. Univariate and multivariate statistical tests were applied to the assembled database to assess differences in outcomes. RESULTS The English language literature contains series with a total of 97 pediatric patients who sustained floating knee injuries. Patients averaged 9.3 years of age and were mostly male (73). Approximately 25% of the fractures were open injuries, more tibia (27) than femur (10). Over 75% of the fractures of both the tibia and the femur involved the diaphysis. More than half (52) of the patients were treated non-operatively for both fractures. As a sequela of the injury 32 (33%) patients were left with a limb length discrepancy, 24 (25%) patients had lengthening of the injured limb at follow up, while 8 (8%) had shortening of the affected limb. Infection developed in 9 patients and 3 had premature physeal closure. Younger patients were more likely to be treated non-operatively (P < 0.001) and patients treated with operative intervention had statistically significant shorter hospital length of stays (P = 0.001). CONCLUSION Given the predominance of non-operative management in published studies, the available literature is not clinically relevant since the popularization of internal fixation for pediatric long-bone fractures