High-Risk Mucosal Human Papillomavirus 16 (HPV16) E6 Protein and Cutaneous HPV5 and HPV8 E6 Proteins Employ Distinct Strategies To Interfere with Interferon Regulatory Factor 3-Mediated Beta Interferon Expression.

Persistent infection with some mucosal α-genus human papillomaviruses (HPVs; the most prevalent one being HPV16) can induce cervical carcinoma, anogenital cancers, and a subset of head and neck squamous cell carcinoma (HNSCC). Cutaneous ß-genus HPVs (such as HPV5 and HPV8) associate with skin lesions that can progress into squamous cell carcinoma with sun exposure in Epidermodysplasia verruciformis patients and immunosuppressed patients. Here, we analyzed mechanisms used by E6 proteins from the α- and ß-genus to inhibit the interferon-ß (IFNB1) response. HPV16 E6 mediates this effect by a strong direct interaction with interferon regulatory factor 3 (IRF3). The binding site of E6 was localized within a flexible linker between the DNA-binding domain and the IRF-activation domain of IRF3 containing an LxxLL motif. The crystallographic structure of the complex between HPV16 E6 and the LxxLL motif of IRF3 was solved and compared with the structure of HPV16 E6 interacting with the LxxLL motif of the ubiquitin ligase E6AP. In contrast, cutaneous HPV5 and HPV8 E6 proteins bind to the IRF3-binding domain (IBiD) of the CREB-binding protein (CBP), a key transcriptional coactivator in IRF3-mediated IFN-ß expression. IMPORTANCE Persistent HPV infections can be associated with the development of several cancers. The ability to persist depends on the ability of the virus to escape the host immune system. The type I interferon (IFN) system is the first-line antiviral defense strategy. HPVs carry early proteins that can block the activation of IFN-I. Among mucosal α-genus HPV types, the HPV16 E6 protein has a remarkable property to strongly interact with the transcription factor IRF3. Instead, cutaneous HPV5 and HPV8 E6 proteins bind to the IRF3 cofactor CBP. These results highlight the versatility of E6 proteins to interact with different cellular targets. The interaction between the HPV16 E6 protein and IRF3 might contribute to the higher prevalence of HPV16 than that of other high-risk mucosal HPV types in HPV-associated cancers.

The height-to-width index for the assessment of femoral head deformity following osteonecrosis in the treatment of developmental dysplasia.

BACKGROUND: The principal complications that follow the treatment of developmental dysplasia of the hip are redislocation and growth disturbance of the femoral head and neck as a result of osteonecrosis of the femoral epiphysis. Growth disturbance secondary to osteonecrosis is difficult to determine until long after the treatment episode has passed. Consequently, the treating surgeon has little early feedback regarding the long-term consequences of management interventions. We therefore sought to devise a quantitative method to identify early evidence of growth disturbance related to osteonecrosis. METHODS: The width and height of the epiphyses were measured on anteroposterior radiographs of the pelvis made twelve to eighteen months after successful closed reduction and on the latest available radiograph for each patient (mean age, 8.6 years). The epiphyseal index was calculated by dividing the height by the width. The radiographs were also scored for osteonecrosis with use of the Kalamchi and MacEwen classification system and were also assessed for sphericity with use of Mose rings. RESULTS: Forty-seven patients with late-presenting developmental dysplasia of the hip who subsequently underwent successful closed reduction were included. An index of <0.357 on the twelve to eighteen-month post-treatment radiograph strongly predicted the development of a nonspherical femoral head on the latest radiograph (sensitivity, 0.83; specificity, 0.95; positive predictive value, 0.55; and negative predictive value, 0.99). CONCLUSIONS: The height-to-width index appears to be a simple and quantifiable measurement of the severity of growth disturbance as a consequence of osteonecrosis following treatment for developmental dysplasia of the hip. It is predictive of asphericity at the time of intermediate-term follow-up and appears likely to predict asphericity at maturity, but this must be confirmed with follow-up to maturity. Unlike the currently used methods of assessing osteonecrosis, the index allows for the quantifiable evaluation of growth disturbance within a few years after the corrective procedure.

Correction of simple and complex pediatric deformities using the Taylor-Spatial Frame.

INTRODUCTION: Correcting multiplanar lower-limb pediatric deformities requires complex and, in many cases, staged procedures. The Taylor-Spatial Frame (TSF) is a sophisticated external fixator system that can be used to treat simple to complex multiplanar and multiapical skeletal deformities. We describe its use in 53 children during the last 7 years in a variety of pathologies and demonstrate its ease of use and versatility. METHODS: A review of medical and physiotherapy records, radiographs, and computed tomographic scans of all patients treated with a TSF between June 1999 and December 2005 at the Booth Hall Children's Hospital was conducted. Data recorded were etiology of deformity, sex, age, number of previous operations, preoperative deformity parameters, operative records and frame constructs, treatment regime, frame duration, follow-up protocol, posttreatment deformity, complications, and clinical and radiological outcome. RESULTS: Fifty-three patients between the ages of 12 months and 16 years (mean, 10.7 years) underwent correction programs for 55 limbs (44 tibia and 11 femurs). The etiology of deformity was congenital in 39 cases and acquired in 14. We were able to achieve an acceptable correction of deformity (leg length discrepancy <15 mm, angulation <5 degrees) in 52 limbs. A number of complications were encountered, which are discussed. DISCUSSION AND CONCLUSION: We demonstrate its ease of use for both surgeon and patient and its versatility in a variety of pathologies. The advantages of the TSF system are many. It is a simple frame construct, and application is easy. The plan and execution are structured with precise end points; it is a single-stage correction and thus avoids frame modifications. Any residual deformity can be further corrected by use of the same frame. We conclude that the TSF is an effective and efficient way to correct a wide variety of simple and complex often obstinate pediatric limb deformities.

A phase I and pharmacokinetic trial of erlotinib in combination with weekly docetaxel in patients with taxane-naive malignancies.

PURPOSE: This study aimed to define the maximum tolerated dose of weekly docetaxel combined with daily erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor. EXPERIMENTAL DESIGN: Patients with any solid tumor received 150 mg erlotinib with escalating doses of docetaxel (20, 25, 30, and 35 mg/m(2)) on days 1, 8, and 15 every 28 days. The pharmacokinetics of docetaxel and erlotinib was determined on cycle 2, day 1. Erlotinib was given for a maximum of 12 cycles and docetaxel was given for up to 6 cycles. RESULTS: Twenty-five patients (17 males and 8 females) were enrolled with a median age of 56 years (range, 34-76); Eastern Cooperative Oncology Group performance status of 0/1 was 20/5. One patient had a dose-limiting toxicity in cycle 1 at the 25 mg/m(2) level (grade 3 enterocolitis). At 35 mg/m(2) docetaxel dose level, 6 of 10 patients required dose reductions to 30 mg/m(2) beyond cycle 1 due to neutropenia (3 patients) and mucositis, increased bilirubin, and diarrhea (1 patient each). The clearance of docetaxel and erlotinib of 61.7 and 8.16 L/h, respectively, did not seem to differ from historical controls. Responses were seen in non-small cell lung cancer, prostate cancer, and hepatobiliary cancers, including a complete response lasting 36+ months in a patient with hepatocellular carcinoma. CONCLUSION: Although no maximum tolerated dose was reached in cycle 1 with 35 mg/m(2) docetaxel, repetitive dosing proved intolerable in a substantial number of patients; thus, the recommended phase II dose of weekly docetaxel is 30 mg/m(2) when combined with 150 mg of daily erlotinib.

A phase I, pharmacokinetic and pharmacodynamic dose escalation trial of weekly paclitaxel with interferon-alpha2b in patients with solid tumors.

PURPOSE: Paclitaxel and interferon have demonstrated anti-angiogenic activity in vitro and in vivo. The toxicity, pharmacokinetics, and pharmacodynamics of paclitaxel with interferon-alpha2b (IFN-alpha2b) were assessed in patients with solid tumors to assess the feasibility of this novel anti-angiogenic regimen. METHODS: IFN-alpha2b (1 million units) was administered twice daily by subcutaneous injection. Paclitaxel was given weekly over 1 h starting at 30 mg/m2 and increased to 50 mg/m2. Cycles were repeated every 4 weeks. RESULTS: Nineteen patients with a variety of solid tumors were enrolled. Dose-limiting toxicity in cycle 1 was observed at 50 mg/m2. Eleven patients were treated at 40 mg/m2 with no undue toxicity. Pharmacokinetic parameter comparison studies were completed in 11 patients who received days 1 and 29 paclitaxel. Mean paclitaxel clearance and area under the curve (0-infinity) were not statistically different from days 1 to 29. There was a 50% increase in the average Cmax from days 1 to 29. There was also a 73% decrease of matrix metalloproteinase-9 (MMP-9) levels in these 11 patients from days 1 to 29 (p < 0.0005). All three patients with cutaneous angiosarcomas experienced clinically meaningful remissions. In addition, minor responses were observed in one patient with heavily pretreated ovarian cancer and another with adrenocortical carcinoma. CONCLUSION: This trial details the inability to dose escalate to the maximum tolerated dose of weekly paclitaxel when combined with low-dose interferon. However, this low-dose regimen caused a significant decrease in MMP-9 and demonstrated anti-cancer activity in cutaneous angiosarcomas.

Extended interval for retrieval of Günther Tulip filters.

PURPOSE: To evaluate the Gunther Tulip vena cava filter with regard to ease of placement, complications, and retrieval over long time periods. MATERIALS AND METHODS: In 53 patients (ratio of men to women, 24:29; mean age, 52.8 years) retrievable Gunther Tulip filters (Vena Cava M Reye Filter Set; William Cook Europe, Denmark) were inserted. Indications included planned major surgery with recent pulmonary embolus or high pulmonary embolus risk (n = 16), extensive ilio-femoral thrombus (n = 11), deep vein thrombosis with anticoagulant complications (n = 9), breakthrough pulmonary embolus despite anticoagulant therapy (n = 4), and contraindication to anticoagulant therapy (n = 13). All patients were followed-up for immediate and long-term complications. RESULTS: Fifty-three filters were successfully placed in 52 of 53 patients, yielding a success rate of 98.1%. Nineteen patients underwent attempted retrieval of their filter. Sixteen of 19 retrieval procedures were successful (84%). In three patients, the filter could not be removed on attempted retrieval (extensive filter thrombus in two patients and attachment to the wall in one patient). One patient received two filters, which were both successfully retrieved at a later date. Median implantation time for retrievable filters was 34 days (range, 7-126 days). Mean follow-up for patients with permanent filters was 13 months. Two major complications (pneumothorax and break through pulmonary embolus) and three minor complications (right internal jugular vein thrombosis in two patients and transient Horner's Syndrome in one patient) were recorded. CONCLUSION: Insertion and retrieval of filters is safe and feasible. Preliminary data suggest that Gunther Tulip filter retrieval is feasible over and above the manufacturer's recommended retrieval interval of 14 days.