Giant phyllodes tumor of the breast: A case report.

Phyllodes tumors of the breast are rare fibroepithelial neoplasms that account for less than 1% of all breast tumors. They tend to affect middle-aged women, who present with a rapidly growing, palpable mass. Here we present a case of a 34-year-old female surrogate mother without any reported personal or family history of breast cancer who presented with a rapidly growing left breast mass, pathologically proven to be a phyllodes tumor. The patient was a G7P7 surrogate mother who received estrogen and progesterone injections for her twin surrogate pregnancy starting 4 months before embryo implantation, after which, she discovered a large palpable mass in the left breast at approximately week 7 gestational age. At the initial presentation, the patient was at week 23 gestational age. She underwent C-section delivery of the twins at this time and obtained further work-up of the mass. She had a core needle biopsy which yielded a benign fibroepithelial tumor. Due to the size of her breast mass and atypical morphology, including extension to the nipple, and skin ulceration, the patient subsequently underwent left mastectomy. At the time of mastectomy, which was 8 months after the initial work-up, the mass had grown to measure approximately 12 × 10 cm on physical examination and took up most of her left breast. It was completely resected and was pathologically determined to be a borderline phyllodes tumor. Only a few cases have been reported about the development of phyllodes tumor during pregnancy in the literature, and we believe this is the first case report of phyllodes tumor related to a surrogate pregnancy. Although the relationship between exogenous hormones and fibroepithelial tumors is not well understood, the case poses the clinical question if screening mammograms should be offered to patients undergoing exogenous hormonal therapy, regardless of age to establish a baseline and monitor for the development (if any) or growth of these tumors.

Enlarging premaxillary mass: A unique manifestation of extranodal diffuse B-cell lymphoma.

Lymphomas are the most common nonepithelial malignancy in the head and neck region. Among these, non-Hodgkin Lymphoma (NHL) is the most prevalent, and diffuse large B-cell lymphoma (DLBCL) is the most common histologic subtype. NHL is known for its propensity for extranodal involvement, which can affect any anatomical location. The presence of perineural spread is frequently encountered in head and neck malignancies, including lymphomas. We report a case of a 40-year-old male with an enlarging infraorbital facial mass with associated erythema, pain, and paresthesia, which was subsequently found to be extranodal DLBCL with retrograde perineural spread along the infraorbital nerve.

Comparison of Outcomes in Percutaneous Fixation of Traumatic Fractures between Ankylosing Spondylitis and Diffuse Idiopathic Skeletal Hyperostosis.

STUDY DESIGN: Retrospective cohort study. OBJECTIVES: This study aims to analyze outcomes and complications of patients with thoracic and lumbar fractures in the setting of ankylosing spinal disorders (ASD) treated with minimally invasive surgery (MIS). METHODS: The operative logs from 2012 to 2019 from one academic, Level I trauma center were reviewed for cases of thoracic and lumbar spinal fractures in patients with ASD treated with a MIS approach. Variables were compared between patients with ankylosing spondylitis (AS), diffuse idiopathic skeletal hyperostosis (DISH), and advanced spondylosis. RESULTS: A total of 48 patients with ASD and concomitant thoracic or lumbar spinal fracture managed with an MIS approach were identified. A total of 11 patients were identified with AS, 21 with DISH, and 16 with advanced spondylosis. A total of 27 (56.3%) patients experienced complications. Complications differed between groups; DISH patients experienced a greater number of post-operative complications compared to AS and advanced spondylosis patients (P = .009). There was no significant difference in length of surgery, estimated blood loss, length of stay, readmission, and reoperation rates between AS and DISH patients. There were 3 mortalities unrelated to the surgery. CONCLUSION: Percutaneous stabilization of patients with ankylosing spinal disorder fractures remains a viable management method. Operative characteristics were similar between AS, DISH, and advanced spondylosis patients; however, DISH patients experienced a greater number of post-operative complications.

Retrospective Analysis of Causes and Risk Factors of 30-Day Readmission After Spine Surgery for Thoracolumbar Trauma.

STUDY DESIGN: Retrospective Case Series. OBJECTIVE: This study aims to evaluate readmission rates, risk factors, and reason for unplanned 30-day readmissions after thoracolumbar spine trauma surgery. METHODS: A retrospective chart review was conducted for patients undergoing operative treatment for thoracic or lumbar trauma with open or minimally invasive surgical approach at a Level 1 urban trauma center. Patients were divided into two groups based on 30-day readmission status. Reason for readmission, reoperation rates, injury type, trauma severity, and incidence of polytrauma were compared between the two groups. RESULTS: A total of 312 patients, 69.9% male with an average age of 47 ± 19 years were included. The readmitted group included 16 patients (5.1%) of which 9 (56%) were readmitted for medical complications and 7 for surgical complications. Wound complications (31.3% of readmissions) were the most common cause of readmission, followed by non-wound related sepsis (18.9% of readmissions). A total of 6 patients (37.5%) required reoperation; 2 instrumentation failures underwent revision surgery, and 4 wound complications underwent irrigation and debridement. Patients with higher Injury Severity Scale (ISS) were more likely to be readmitted (27.8% vs 22.1%, P = .045). Concomitant lower limb surgery increased odds of readmission (OR, 4.40; 95% CI, 1.10-17.83; P = .037). CONCLUSION: Spine trauma 30-day readmission rate was 5.1%, comparable to those reported in the elective spine surgery literature. Readmitted patients were more likely to sustain concomitant operative lower limb trauma. Wound complications were the most common cause of readmission, and almost half of the patients were readmitted due to surgery-related complications.

Catastrophic acute failure of pelvic fixation in adult spinal deformity requiring revision surgery: a multicenter review of incidence, failure mechanisms, and risk factors.

OBJECTIVE: There are few prior reports of acute pelvic instrumentation failure in spinal deformity surgery. The objective of this study was to determine if a previously identified mechanism and rate of pelvic fixation failure were present across multiple institutions, and to determine risk factors for these types of failures. METHODS: Thirteen academic medical centers performed a retrospective review of 18 months of consecutive adult spinal fusions extending 3 or more levels, which included new pelvic screws at the time of surgery. Acute pelvic fixation failure was defined as occurring within 6 months of the index surgery and requiring surgical revision. RESULTS: Failure occurred in 37 (5%) of 779 cases and consisted of either slippage of the rods or displacement of the set screws from the screw tulip head (17 cases), screw shaft fracture (9 cases), screw loosening (9 cases), and/or resultant kyphotic fracture of the sacrum (6 cases). Revision strategies involved new pelvic fixation and/or multiple rod constructs. Six patients (16%) who underwent revision with fewer than 4 rods to the pelvis sustained a second acute failure, but no secondary failures occurred when at least 4 rods were used. In the univariate analysis, the magnitude of surgical correction was higher in the failure cohort (higher preoperative T1-pelvic angle [T1PA], presence of a 3-column osteotomy; p < 0.05). Uncorrected postoperative deformity increased failure risk (pelvic incidence-lumbar lordosis mismatch > 10°, higher postoperative T1PA; p < 0.05). Use of pelvic screws less than 8.5 mm in diameter also increased the likelihood of failure (p < 0.05). In the multivariate analysis, a larger preoperative global deformity as measured by T1PA was associated with failure, male patients were more likely to experience failure than female patients, and there was a strong association with implant manufacturer (p < 0.05). Anterior column support with an L5-S1 interbody fusion was protective against failure (p < 0.05). CONCLUSIONS: Acute catastrophic failures involved large-magnitude surgical corrections and likely resulted from high mechanical strain on the pelvic instrumentation. Patients with large corrections may benefit from anterior structural support placed at the most caudal motion segment and multiple rods connecting to more than 2 pelvic fixation points. If failure occurs, salvage with a minimum of 4 rods and 4 pelvic fixation points can be successful.

Open vs Percutaneous Pedicle Instrumentation for Kyphosis Correction in Traumatic Thoracic and Thoracolumbar Spine Injuries.

OBJECTIVES: Percutaneous pedicle instrumentation (PPI) has been used for the treatment of thoracic and thoracolumbar (TL) trauma. However, the ability of PPI to correct significant post-traumatic kyphosis requires further investigation. The objective of this study is to compare the amount of kyphosis correction achieved by PPI vs the traditional open posterior approach in patients presenting with significant kyphotic deformity following traumatic thoracic and TL spine injuries. METHODS: Following Institutional Review Board approval, patients who underwent surgery for thoracic (T1-T9) or TL (T10-L2) fractures with at least 15° of focal kyphosis in a 5-year period were included in this study. Patients were separated into 2 cohorts based on surgical technique: traditional open posterior approach and minimally invasive PPI. Kyphosis correction was measured using Cobb angle 1 vertebrae above and 1 below the level of injury on sagittal preoperative computed tomography image, immediate and follow-up postoperative upright lateral radiographs. Initial degree of correction and loss of correction at the final follow-up were compared. RESULTS: Of 91 patients included, 65 (71%) underwent open surgery and 26 (29%) underwent PPI. Open patients had 11° (95% CI, 9°-13°) of immediate correction compared with 11° (95% CI, 6°-15°) for PPI (P = 0.81). Follow-up data were available for 70 patients with a median of 105.5 days. Both groups had 1° (95% CI, 0°-2°) of loss of correction at follow-up (P = 0.82). Regardless of surgical technique, obesity (>30 kg/m2) and AO type-A compression fractures had significantly less correction. For each unit of body mass index, there was a 0.75° decrease in correction achieved (P < 0.0001). Other factors did not influence the degree of correction. CONCLUSIONS: PPI techniques provide equivalent postoperative angular correction and maintenance of correction compared with open surgery in thoracic and TL trauma patients. CLINICAL RELEVANCE: This study provides evidence for spine surgeons to utilize either technique for treating significant traumatic kyphotic deformity. LEVEL OF EVIDENCE: Therapeutic 3.

Predicting Length of Stay After Thoracolumbar Trauma: A Single-Center, Retrospective Analysis.

BACKGROUND: Length of stay (LOS) is a meaningful outcome measure for more efficient and effective quality of care. However, algorithms to predict LOS have yet to be created for patients who undergo surgical management for traumatic spinal fractures. OBJECTIVES: The objectives of this study were to (1) identify preoperative, perioperative, and postoperative factors associated with increased LOS and (2) create predictive formulas to estimate LOS in thoracolumbar trauma patients who undergo surgical correction. METHODS: This is a retrospective case series of 196 patients operated for thoracolumbar spine trauma from January 2012 to December 2017 at a level 1 trauma and academic institution. Bivariate analysis between LOS and various preoperative, perioperative, and postoperative factors was conducted to identify significant associations. Multivariate analysis was conducted to create models capable of predicting LOS. RESULTS: LOS was significantly associated with various preoperative (eg, Charlson Comorbidity Index, Glasgow Coma Scale [GCS], injury severity score), operative (eg, length of surgery, number of instrumented segments, surgical technique), and postoperative variables (eg, complications, discharge location). Multivariate analysis of preoperative variables identified 5 significant independent predictors that could predict LOS with strong correlation with observed LOS (ρ = 0.63). With all variables considered, multivariate analysis identified 8 variables (GCS, American Society of Anesthesiologists score, neurological status, polytrauma, packed red blood cell transfusion, number of unique postoperative complications, skin complications, and discharge facility) that could predict LOS with strong correlation (ρ = 0.80). CONCLUSIONS: Various preoperative, perioperative, and postoperative factors are significantly associated with LOS in traumatic thoracolumbar spine patients. We developed models with good predictive capacity for LOS. If validated, these models should help in risk stratifying patients for increased LOS and consequently improve perioperative patient counseling. CLINICAL RELEVANCE: This article contributes to identifying and predicting patients who are high risk for extended LOS after traumatic thoracolumbar injuries.

Postoperative outcomes of minimally invasive pedicle screw fixation for treatment of unstable pathologic neoplastic fractures.

STUDY DESIGN: Retrospective Case Series. OBJECTIVES: Minimally invasive techniques have emerged as a useful tool in the treatment of neoplastic spine pathology due to decrease in surgical morbidity and earlier adjuvant treatment. The objective of this study was to analyze outcomes and complications in a cohort of unstable, symptomatic pathologic fractures treated with percutaneous pedicle screw fixation (PPSF). METHODS: A retrospective review was performed on consecutive patients with spinal stabilization for unstable pathologic neoplastic fractures between 2007 and 2017. Patients who underwent PPSF through a minimally invasive approach were included. Surgical indications included intractable pain, mechanical instability, and neurologic compromise with radiologic visualization of the lesion. RESULTS: 20 patients with mean Tomita Score of 6.3 ± 2.1 points [95% CI, 5.3-7.2] were treated with constructs that spanned a mean of 4.7 ± 1.4 [95% CI, 4.0-5.3] instrumented levels. 10 (50%) patients were augmented with vertebroplasty. Majority of patients (65%) had no complications during their hospital stay and were discharged home (60%). Four patients received reoperation: two extracavitary corpectomies, one pathologic fracture at a different level, and one adjacent segment disease. CONCLUSION: Minimally invasive PPSF is a safe and effective option when treating unstable neoplastic fractures and may be a viable alternative to the traditional open approach in select cases. LEVEL OF EVIDENCE: 4.

Effect of Surgical Setting on Cost and Hospital Reported Outcomes for Single-Level Anterior Cervical Discectomy and Fusion.

BACKGROUND: Hospitals seek to reduce costs and improve patient outcomes by decreasing length of stay (LOS), 30-day all-cause readmissions, and preventable complications. We evaluated hospital-reported outcome measures for elective single-level anterior cervical discectomy and fusions (ACDFs) between tertiary (TH) and community hospitals (CH) to determine location-based differences in complications, LOS, and overall costs. METHODS: Patients undergoing elective single-level ACDF in a 1-year period were retrospectively reviewed from a physician-driven database from a single medical system consisting of 1 TH and 4 CHs. Adult patients who underwent elective single-level ACDF were included. Patients with trauma, tumor, prior cervical surgery, and infection were excluded. Outcomes measures included all-cause 30-day readmissions, preventable complications, LOS, and hospital costs. RESULTS: A total of 301 patients (60 TH, 241 CH) were included. CHs had longer LOS (1.25 ± 0.50 versus 1.08 ± 0.28 days, P = .01). There were no differences in complication and readmission rates between hospital settings. CH, orthopaedic subspecialty, female sex, and myelopathy were predictors for longer LOS. Overall, costs at the TH were significantly higher than at CHs ($17 171 versus $11 737; Δ$ = 5434 ± 3996; P < .0001). For CHs, the total costs of drugs, rooms, supplies, and therapy were significantly higher than at the TH. TH status, orthopaedic subspecialty, and myelopathy were associated with higher costs. CONCLUSION: Patients undergoing single-level ACDFs at CHs had longer LOS, but similar complications and readmission rates as those at the TH. However, cost of ACDF was 1.5 times greater in the TH. To improve patient outcomes, optimize value, and reduce hospital costs, modifiable factors for elective ACDFs should be evaluated. LEVEL OF EVIDENCE: 3.

Dural Tear Does not Increase the Rate of Venous Thromboembolic Disease in Patients Undergoing Elective Lumbar Decompression with Instrumented Fusion.

OBJECTIVE: Evaluate if dural tears (DTs) are an indirect risk factor for venous thromboembolic disease through increased recumbency in patients undergoing elective lumbar decompression and instrumented fusion. METHODS: This was a retrospective cohort study of consecutive patients undergoing elective lumbar decompression and instrumented fusion at a single institution between 2016 and 2019. Patients were divided into cohorts: those who sustained a dural tear and those who did not. The cohorts were compared using Student's t-test or Wilcoxon Rank Sum for continuous variables and Fisher exact or chi-squared test for nominal variables. RESULTS: Six-hundred and eleven patients met inclusion criteria, among which 144 patients (23.6%) sustained a DT. The DT cohort tended to be older (63.6 vs. 60.6 years, P = 0.0052) and have more comorbidities (Charlson Comorbidity Index 2.75 vs. 2.35, P = 0.0056). There was no significant difference in the rate of symptomatic deep vein thrombosis (2.1% vs. 2.6%, P = 1.0) or pulmonary embolus (1.4% vs. 1.50%, P = 1.0). Intraoperatively, DT was associated with increased blood loss (754 mL vs. 512 mL, P < 0.0001), operative time (224 vs. 195 minutes, P < 0.0001), and rate of transfusion (19.4% vs. 9.4%, P = 0.0018). Postoperatively, DT was associated with increased time to ambulation (2.6 vs. 1.4 days, P < 0.0001), length of stay (5.8 vs. 4.0 days, P < 0.0001), and rate of discharge to rehab (38.9 vs. 25.3%, P = 0.0021). CONCLUSIONS: While DTs during elective lumbar decompression and instrumentation led to later ambulation and longer hospital stays, the increased recumbency did not significantly increase the rate of symptomatic venous thromboembolic disease.

The Prevalence of Bacterial Infection in Patients Undergoing Elective ACDF for Degenerative Cervical Spine Conditions: A Prospective Cohort Study With Contaminant Control.

STUDY DESIGN: Prospective cohort study. OBJECTIVES: To determine the prevalence of bacterial infection, with the use of a contaminant control, in patients undergoing anterior cervical discectomy and fusion (ACDF). METHODS: After institutional review board approval, patients undergoing elective ACDF were prospectively enrolled. Samples of the longus colli muscle and disc tissue were obtained. The tissue was then homogenized, gram stained, and cultured in both aerobic and anaerobic medium. Patients were classified into 4 groups depending on culture results. Demographic, preoperative, and postoperative factors were evaluated. RESULTS: Ninety-six patients were enrolled, 41.7% were males with an average age of 54 ± 11 years and a body mass index of 29.7 ± 5.9 kg/m2. Seventeen patients (17.7%) were considered true positives, having a negative control and positive disc culture. Otherwise, no significant differences in culture positivity was found between groups of patients. However, our results show that patients were more likely to have both control and disc negative than being a true positive (odds ratio = 6.2, 95% confidence interval = 2.5-14.6). Propionibacterium acnes was the most commonly identified bacteria. Two patients with disc positive cultures returned to the operating room secondary to pseudarthrosis; however, age, body mass index, prior spine surgery or injection, postoperative infection, and reoperations were not associated with culture results. CONCLUSION: In our cohort, the prevalence of subclinical bacterial infection in patients undergoing ACDF was 17.7%. While our rates exclude patients with positive contaminant control, the possibility of contamination of disc cultures could not be entirely rejected. Overall, culture results did not have any influence on postoperative outcomes.

Evaluation of Risk Factors for Postoperative Urinary Retention in Elective Thoracolumbar Spinal Fusion Patients.

STUDY DESIGN: Retrospective case series. OBJECTIVES: Postoperative urinary retention (POUR) represents a common postoperative complication of all elective surgeries. The aim of this study was to identify demographic, comorbid, and surgical factors risk factors for POUR in patients who underwent elective thoracolumbar spine fusion. METHODS: Following institutional review board approval, patients who underwent elective primary or revision thoracic and lumbar instrumented spinal fusion in a 2-year period in tertiary and academic institution were reviewed. Sex, age, BMI, preoperative diagnosis, comorbid conditions, benign prostatic hyperplasia, diabetes, primary or revision surgery status, narcotic use, and operative factors were collected and analyzed between patients with and without POUR. RESULTS: Of the 217 patients reviewed, 54 (24.9%) developed POUR. The average age for a patient with POUR was 67 ± 9, as opposed to 59 ± 10 for those without (P < .0001). Single-level fusions were associated with a 0% incidence of POUR, compared with 54.5% in 6 or more levels. The average hospital stay was increased by 1 day for those who had POUR (5.8 ± 3.3 vs 4.9 ± 3.9 days). There was no significant association with other demographic variables, comorbid conditions, or surgical factors. CONCLUSIONS: POUR was a common complication in our patient cohort, with an incidence of 24.9%. Our findings demonstrate that patients who developed POUR are significantly older and have larger constructs. Patients who developed POUR also had longer in-hospital stays. Although our study supports other findings in the spine literature, more prospective data is needed to define diagnostic criteria of POUR as well as its management.

Impact of Preoperative Platelet Count on Bleeding Risk and Allogeneic Transfusion in Multilevel Spine Surgery.

STUDY DESIGN: This was an observational cohort study of patients receiving multilevel thoracic and lumbar spine surgery. OBJECTIVE: The aim of this study was to identify which patients are at high risk for allogeneic transfusion which may allow for better preoperative planning and employment of specific blood management strategies. SUMMARY OF BACKGROUND DATA: Multilevel posterior spine surgery is associated with a significant risk for major blood loss, and allogeneic blood transfusion is common in spine surgery. METHODS: A univariate logistic regression model was used to identify variables that were significantly associated with intraoperative allogeneic transfusion. A multivariate forward stepwise logistic regression model was then used to measure the adjusted association of these variables with intraoperative transfusion. RESULTS: Multilevel thoracic and lumbar spine surgery was performed in 921 patients. When stratifying patients by preoperative platelet count, patients with pre-operative thrombocytopenia and severe thrombocytopenia had a significantly higher rate of transfusion than those who were not thrombocytopenic. Furthermore, those with severe thrombocytopenia had a higher rate of red blood cells, fresh frozen plasma, and platelet transfusion than those with higher platelet counts. Multivariate logistic regression found that preoperative platelet count was the most significant contributor to transfusion, with a platelet count ≤100 having an adjusted odds ratio (OR) of transfusion of 4.88 (95% confidence interval [CI] 1.58-15.02, P = 0.006). Similarly, a platelet count between 101and 150 also doubled the risk of transfusion with an adjusted OR of 2.02 (95% CI 1.01-4.04, P = 0.047). The American Society of Anesthesiologists classification score increased the OR of transfusion by 2.5 times (OR = 2.52, 95% CI 1.54-4.13), whereas preoperative prothrombin time and age minimally increased the risk. CONCLUSION: Preoperative thrombocytopenia significantly contributes to intraoperative transfusion in multilevel thoracic lumbar spine surgery. Identifying factors that may increase the risk for transfusion could be of great benefit in better preoperative counseling of patients and in reducing overall cost and postoperative complications by implementing strategies and techniques to reduce blood loss and blood transfusions. LEVEL OF EVIDENCE: 2.

Comparison of percutaneous minimally invasive versus open posterior spine surgery for fixation of thoracolumbar fractures: A retrospective matched cohort analysis.

INTRODUCTION: Percutaneous minimally invasive spine surgery (MISS) is a treatment option for thoracolumbar fractures and we aim to evaluate its outcomes. METHODS: A retrospective matched cohort study of all patients with thoracolumbar fractures treated with MISS or open posterior approach. RESULTS: We included 100 MISS and 155 open patients. After controlling for patient characteristics, our results statistically favor MISS in mean operative time, mean intraoperative blood loss, and number of patients requiring postoperative blood transfusions within 48 h. CONCLUSIONS: Advantages of using MISS for treatment of thoracolumbar fractures are decreased operative time, decreased blood loss, and fewer patients requiring transfusions.

Silymarin Suppresses Cellular Inflammation By Inducing Reparative Stress Signaling.

Silymarin, a characterized extract of the seeds of milk thistle (Silybum marianum), suppresses cellular inflammation. To define how this occurs, transcriptional profiling, metabolomics, and signaling studies were performed in human liver and T cell lines. Cellular stress and metabolic pathways were modulated within 4 h of silymarin treatment: activation of Activating Transcription Factor 4 (ATF-4) and adenosine monophosphate protein kinase (AMPK) and inhibition of mammalian target of rapamycin (mTOR) signaling, the latter being associated with induction of DNA-damage-inducible transcript 4 (DDIT4). Metabolomics analyses revealed silymarin suppression of glycolytic, tricarboxylic acid (TCA) cycle, and amino acid metabolism. Anti-inflammatory effects arose with prolonged (i.e., 24 h) silymarin exposure, with suppression of multiple pro-inflammatory mRNAs and signaling pathways including nuclear factor kappa B (NF-κB) and forkhead box O (FOXO). Studies with murine knock out cells revealed that silymarin inhibition of both mTOR and NF-κB was partially AMPK dependent, whereas silymarin inhibition of mTOR required DDIT4. Other natural products induced similar stress responses, which correlated with their ability to suppress inflammation. Thus, natural products activate stress and repair responses that culminate in an anti-inflammatory cellular phenotype. Natural products like silymarin may be useful as tools to define how metabolic, stress, and repair pathways regulate cellular inflammation.

Direct, interferon-independent activation of the CXCL10 promoter by NF-κB and interferon regulatory factor 3 during hepatitis C virus infection.

Hepatitis C virus (HCV) infection of hepatocytes leads to transcriptional induction of the chemokine CXCL10, which is considered an interferon (IFN)-stimulated gene. However, we have recently shown that IFNs are not required for CXCL10 induction in hepatocytes during acute HCV infection. Since the CXCL10 promoter contains binding sites for several proinflammatory transcription factors, we investigated the contribution of these factors to CXCL10 transcriptional induction during HCV infection in vitro. Wild-type and mutant CXCL10 promoter-luciferase reporter constructs were used to identify critical sites of transcriptional regulation. The proximal IFN-stimulated response element (ISRE) and NF-κB binding sites positively regulated CXCL10 transcription during HCV infection as well as following exposure to poly(I·C) (a Toll-like receptor 3 [TLR3] stimulus) and 5' poly(U) HCV RNA (a retinoic acid-inducible gene I [RIG-I] stimulus) from two viral genotypes. Conversely, binding sites for AP-1 and CCAAT/enhancer-binding protein ß (C/EBP-ß) negatively regulated CXCL10 induction in response to TLR3 and RIG-I stimuli, while only C/EBP-ß negatively regulated CXCL10 during HCV infection. We also demonstrated that interferon-regulatory factor 3 (IRF3) is transiently recruited to the proximal ISRE during HCV infection and localizes to the nucleus in HCV-infected primary human hepatocytes. Furthermore, IRF3 activated the CXCL10 promoter independently of type I or type III IFN signaling. The data indicate that sensing of HCV infection by RIG-I and TLR3 leads to direct recruitment of NF-κB and IRF3 to the CXCL10 promoter. Our study expands upon current knowledge regarding the mechanisms of CXCL10 induction in hepatocytes and lays the foundation for additional mechanistic studies that further elucidate the combinatorial and synergistic aspects of immune signaling pathways.