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.

Background With increasing prevalence of methicillinresistant Staphylococcus aureus (MRSA) in patients undergoing hip and knee arthroplasty, some have advocated a dual-antibiotic regimen including vancomycin as prophylaxis against surgical site infections. However, routine administration of vancomycin may result in impaired renal functions in susceptible patients. Questions/purposes The purpose of this study was to determine whether patients receiving antibiotic prophylaxis with cefazolin and vancomycin have a higher risk of postoperative acute kidney injury (AKI) compared with patients receiving cefazolin alone before elective primary hip and knee arthroplasty. We also aimed to compare severity and recovery of AKI in these two cohorts and to determine independent risk factors for AKI. Methods We retrospectively evaluated a series of 1828 patients undergoing primary hip and knee arthroplasty over a 2-year period who received either cefazolin (n = 500) or cefazolin and vancomycin (n = 1328) as perioperative antibiotic prophylaxis. During the study period, a perceived high prevalence of MRSA infections at our institution led some surgeons to add vancomycin to the prophylactic antibiotic regimen. The patient characteristics, case mix, and preoperative renal function and baseline creatinine clearance were similar between the two groups. We defined AKI according to the published Acute Kidney Injury Network (AKIN) criteria, and the risk of AKI in both groups was compared. We also compared the proportions of patients by AKIN severity stage and assessed recovery as defined by creatinine levels showing kidney function reaching 50% baseline. The American Society of Anesthesiologists (ASA) classification, preoperative chronic kidney disease, intraoperative fluid requirements, and estimated blood loss were recorded. We analyzed the data using a multivariate logistic regression model to identify potential independent risk factors, including dual antibiotic therapy. Results Patients receiving dual antibiotics were more likely to develop AKI compared with those receiving cefazolin alone (13% versus 8%, p = 0.002). Dual-antibiotic prophylaxis also was associated with greater severity; patients in the dual antibiotic group had higher rates of Grade II and III acute kidney injury (3% versus 0%, p = 0.003). There was no difference in the rate of return to baseline renal function (2 ± 1.4 days versus 3 ± 3.4 days; mean difference, 0.5 days; 95% confidence interval [CI], À0.2 to 1.2 days; p = 0.155). Controlling for confounding variables, dual antibiotic prophylaxis (adjusted odds ratio [OR], 1.82; 95% CI, 1.25-2.64; p = 0.002), ASA class

Background: Anterior vertebral body tethering (AVBT) is a growth-modulation technique theorized to correct adolescent idiopathic scoliosis (AIS) without the postoperative stiffness imposed by posterior spinal fusion. However, data are limited to small series examining short-term outcomes. To assess AVBT’s potential as a viable alternative to posterior spinal fusion (PSF), a comprehensive comparison is warranted. The purpose of this meta-analysis was to compare postoperative outcomes between patients with AIS undergoing PSF and AVBT. Our primary objective was to compare complication and reoperation rates at available follow-up times. Secondary objectives included comparing mid-term Scoliosis Research Society (SRS)-22 scores, and coronal and sagittal-plane Cobb angle corrections. Methods: We performed a systematic review of outcome studies following AVBT and/or PSF procedures. The inclusion criteria included the following: AVBT and/or PSF procedures; Lenke 1 or 2 curves; an age of 10 to 18 years for >90% of the patient population; <10% non-AIS scoliosis etiology; and follow-up of ≥1 year. A single-arm, random-effects meta-analysis was performed. Deformity corrections, complication and reoperation rates, and postoperative SRS-22 scores were recorded. Results: Ten AVBT studies (211 patients) and 14 PSF studies (1,069 patients) were included. The mean follow-up durations were similar for both groups. Pooled complication rates were 26% for AVBT versus 2% for PSF, and reoperation rates were 14.1% for AVBT versus 0.6% for PSF with nonoverlapping confidence intervals (CIs). The pooled reoperation rate among studies with follow-up times of ≥36 months was 24.7% in AVBT versus 1.8% in PSF. Deformity correction, clinical outcomes, and mid-term SRS-22 scores were similar. Conclusions: Our study showed greater rates of complications and reoperations with AVBT compared with PSF. Reoperation rates were significantly greater in AVBT studies with longer follow-up (≥36 months). Deformity correction, clinical outcomes, and mid-term SRS-22 scores were similar. While a potential fusionless treatment for AIS merits excitement, clinicians should consider AVBT with caution. Future long-term randomized prospective studies are needed. Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.