Population pharmacokinetics and exposure-response of trastuzumab emtansine in advanced breast cancer previously treated with ≥2 HER2-targeted regimens.

AIMS: We conducted population pharmacokinetic (PopPK) and exposure-response analyses for trastuzumab emtansine (T-DM1), to assess the need for T-DM1 dose optimization in patients with low exposure by using TH3RESA [A Study of Trastuzumab Emtansine in Comparison With Treatment of Physician's Choice in Patients With human epidermal growth factor receptor 2 (HER2)-positive Breast Cancer Who Have Received at Least Two Prior Regimens of HER2-directed Therapy] study data (NCT01419197). The randomized phase III TH3RESA study investigated T-DM1 vs. treatment of physician's choice (TPC) in patients with heavily pretreated HER2-positive advanced breast cancer. METHODS: We compared a historical T-DM1 PopPK model with T-DM1 pharmacokinetics in TH3RESA and performed exposure-response analyses using model-predicted cycle 1 maximum concentration (Cmax ), cycle 1 minimum concentration (Cmin ) and area under the concentration-time curve at steady state (AUCss ). Kaplan-Meier analyses [overall survival (OS), progression-free survival (PFS)] and logistic regression [overall response rate (ORR), safety] were stratified by T-DM1 exposure metrics. Survival hazard ratios (HRs) in the lowest exposure quartile (Q1) of cycle 1 Cmin were compared with matched TPC-treated patients. RESULTS: T-DM1 concentrations in TH3RESA were described well by the historical PopPK model. Patients with higher cycle 1 Cmin and AUCss exhibited numerically longer median OS and PFS and higher ORR than patients with lower exposure. Exposure-response relationships were less evident for cycle 1 Cmax . No relationship between exposure and safety was identified. HRs for the comparison of T-DM1-treated patients in the Q1 subgroup with matched TPC-treated patients were 0.96 [95% confidence interval (CI) 0.63, 1.47] for OS and 0.92 (95% CI 0.64, 1.32) for PFS. CONCLUSIONS: Exposure-response relationships for efficacy were inconsistent across exposure metrics. HRs for survival in patients in the lowest T-DM1 exposure quartile vs. matched TPC-treated patients suggest that, compared with TCP, the approved T-DM1 dose is unlikely to be detrimental to patients with low exposure.

Phase 1b/2a study of trastuzumab emtansine (T-DM1), paclitaxel, and pertuzumab in HER2-positive metastatic breast cancer.

BACKGROUND: In pre-clinical studies, the anti-tumor activity of T-DM1 was enhanced when combined with taxanes or pertuzumab. This phase 1b/2a study evaluated the safety/tolerability of T-DM1 + paclitaxel ± pertuzumab in HER2-positive advanced breast cancer. METHODS: In phase 1b (n = 60), a 3 + 3 dose-escalation approach was used to determine the maximum tolerated dose (MTD) of T-DM1 + paclitaxel ± pertuzumab. The primary objective of phase 2a was feasibility, with 44 patients randomized to T-DM1 + paclitaxel ± pertuzumab at the MTD identified in phase 1b. RESULTS: The MTD was T-DM1 3.6 mg/kg every three weeks (q3w) or 2.4 mg/kg weekly + paclitaxel 80 mg/m(2) weekly ± pertuzumab 840 mg loading dose followed by 420 mg q3w. Phase 2a patients had received a median of 5.0 (range: 0-10) prior therapies for advanced cancer. In phase 2a, 51.2 % received ≥12 paclitaxel doses within 15 weeks, and 14.0 % received 12 paclitaxel doses by week 12. Common all-grade adverse events (AEs) were peripheral neuropathy (90.9 %) and fatigue (79.5 %). A total of 77.3 % experienced grade ≥3 AEs, most commonly neutropenia (25.0 %) and peripheral neuropathy (18.2 %). Among the 42 phase 2a patients with measurable disease, the objective response rate (ORR) was 50.0 % (95 % confidence interval (CI) 34.6-65.4); the clinical benefit rate (CBR) was 56.8 % (95 % CI 41.6-71.0). No pharmacokinetic interactions were observed between T-DM1 and paclitaxel. CONCLUSIONS: This regimen showed clinical activity. Although there is potential for paclitaxel to be added to T-DM1 ± pertuzumab, peripheral neuropathy was common in this heavily pretreated population. TRIAL REGISTRATION: ClinicalTrials.gov NCT00951665 . Registered August 3, 2009.

Analysis of safety data in clinical trials using a recurrent event approach.

As an important aspect of the clinical evaluation of an investigational therapy, safety data are routinely collected in clinical trials. To date, the analysis of safety data has largely been limited to descriptive summaries of incidence rates or contingency tables aiming to compare simple rates between treatment arms. Many have argued that this traditional approach failed to take into account important information including severity, onset time, and multiple occurrences of a safety event. In addition, premature treatment discontinuation due to excessive toxicity causes informative censoring and may lead to potential bias in the interpretation of safety events. In this article, we propose a framework to summarize safety data with mean frequency function and compare safety events of interest between treatments with a generalized log-rank test, taking into account the aforementioned characteristics ignored in traditional analysis approaches. In addition, a multivariate generalized log-rank test to compare the overall safety profile of different treatments is proposed. In the proposed method, safety events are considered to follow a recurrent event process with a terminal event for each patient. The terminal event is modeled by a process of two types of competing risks: safety events of interest and other terminal events. Statistical properties of the proposed method are investigated via simulations. An application is presented with data from a phase II oncology trial.

Quantitative measurement of the androgen receptor in prepuces of boys with and without hypospadias.

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Despite diverse anatomical and histological trials in humans and animal models, the aetiology of hypospadias remains unknown and currently there is no clear molecular explanation about the emergence of this disease; however, genetic, endocrine and environmental mechanisms have been suggested. The aim of the present study was to quantify and compare the androgen receptor (AR; mRNA and protein) levels in 40 prepuces of boys with and without hypospadias using quantitative real-time polymerase chain reaction, Western Blot and standardised, automated immunohistochemistry. AR mRNA (P = 0.013) and AR protein (P = 0.014) was significantly elevated in the prepuces of boys with hypospadias compared with boys without hypospadias. Altogether our data indicate that elevated AR mRNA and protein levels can be considered as a biochemical response of an AR signalling defect as an identified cause in boys with hypospadias. Additionally, nuclear staining intensity for AR-protein in specimens of boys with hypospadias was higher than in boys with phimosis. OBJECTIVE: To address the role of the androgen receptor (AR) on mRNA and protein levels in prepuces of boys with and without hypospadias. PATIENTS AND METHODS: Data from 40 foreskin specimens of consecutive circumcised boys (20 with vs 20 without hypospadias) were enrolled in this prospective study. After surgery, samples were fixed in formaldehyde and frozen in liquid nitrogen. Total RNA was isolated from frozen tissue and transcribed to complementary DNA. The amount of AR mRNA was measured by quantitative real-time polymerase chain reaction and Western Blot and standardised, automated immunohistochemistry were used to assess AR protein levels. RESULTS: The mean age at time of surgery was 61.8 and 30.9 months in boys without and with hypospadias, respectively. There was penile, coronal and sine hypospadias in seven (35%), nine (45%), and four (20%) boys, respectively. AR mRNA was significantly elevated in the prepuces of boys with hypospadias compared with boys without hypospadias, at a mean (sd) of 28.33 (5.39) vs 15.31 (1.85) (P = 0.013). Furthermore, the amount of AR protein was higher in boys with, compared with boys without hypospadias, at a mean (sd) of 133.25 (6.17) vs 100 (4.45) (P = 0.014). CONCLUSIONS: Different AR mRNA expression and protein levels seem to be an indication of an AR signalling defect as a cause in boys with hypospadias. Decreased AR DNA binding and functional capability may result in a compensatory up-regulation of both AR mRNA and protein. Further studies are necessary to perform structural analysis of the AR and to corroborate these preliminary findings.

Head position angles to open the upper airway differ less with the head positioned on a support.

INTRODUCTION: The aim of the study was to assess the effects of positioning the head on a support on "head position angles" to optimally open the upper airway during bag-valve mask ventilation. METHODS: We ventilated the lungs of anesthetized adults with a bag-valve mask and the head positioned with (n = 30) or without a support (n = 30). In both groups, head position angles and ventilation parameters were measured with the head positioned in (1) neutral position, (2) in a position deemed optimal for ventilation by the investigator, and (3) in maximal extension. RESULTS: Between groups ("head with/without a support") and between head positions within each group, head position angles and ventilation parameters differed (P < .0001, respectively). However, head position angles and ventilation parameters between head positions differed less "with a support" (P < .001), and ventilation parameters improved with a support compared with the head-without-a-support group (P < .001). CONCLUSIONS: In the head-with-a-support group, when compared with the head-without-a-support group, head position angles differed less, indicating a decreased potential for failure during bag-valve mask ventilation with the head on a support. Moreover, in the head-with-a-support group, ventilation parameters differed less between head positions, and ventilation improved. These findings suggest a potential benefit of positioning the head on a support during bag-valve mask ventilation.

Need for long-term follow-up in enterohemorrhagic Escherichia coli-associated hemolytic uremic syndrome due to late-emerging sequelae.

BACKGROUND: The aim of this study was to evaluate the long-term prognosis of children with hemolytic uremic syndrome (HUS). METHODS: Over a 6-year period, 619 pediatric patients with the clinical diagnosis of HUS were registered in Austria and Germany, and a subset (n = 274) was prospectively followed up for 5 years. RESULTS: Infection with enterohemorrhagic Escherichia coli (EHEC) was confirmed in 79% of cases. Five years after diagnosis, 70% of EHEC-infected patients (95% confidence interval [CI], .63-.76) were fully recovered. The remaining 30% had persistent hypertension (9%), neurological symptoms (4%), decreased glomerular filtration rate (7%), and/or proteinuria (18%). Hypertension and proteinuria developed in a total of 18% of patients who had no sequelae 1 year after the acute phase (95% CI, 12-26). Multivariate logistic regression analysis demonstrated an association between the use of plasma therapy during acute phase and poor long-term outcome (odds ratio, 2.9-13; 95% CI, 2.4-33; P < .05), but this treatment was also used more frequently in severe cases. In contrast, the use of antibiotic therapy in the diarrheal phase and other established risk factors for developing HUS, such as Shiga toxin 2 and EHEC serotypes traditionally considered to be "high risk," were not associated with adverse long-term outcome. In particular, there was no difference between O157 and non-O157 EHEC. CONCLUSIONS: This study identified an association between the use of plasma treatment and poor long-term outcome and confirms already known risk factors for poor prognosis. Follow-up investigations for at least 5 years are recommended to detect late-emerging sequelae.

Comprehensive analysis of frequency and phenotype of T regulatory cells in HIV infection: CD39 expression of FoxP3+ T regulatory cells correlates with progressive disease.

There are conflicting data about the frequency and role of regulatory T cells (Tregs) during the course of HIV infection. Peripheral blood of a large cohort of HIV-infected patients (n = 131) at different stages of disease, including 15 long-term nonprogressors and 21 elite controllers, was analyzed to determine the frequency and phenotype of Tregs, defined as CD4(+), CD25(high), CD127(low), FoxP3(high) cells. A significantly increased relative frequency of Tregs within the CD4(+) compartment of HIV(+) patients compared to that of healthy controls (P < 0.0001) was observed. Additionally, the relative frequency of Tregs directly correlated with HIV viral load and inversely with CD4(+) counts. However, the absolute Treg number was reduced in HIV-infected patients versus healthy controls (P < 0.0001), with the exception of elite controllers (P > 0.05). The loss of absolute Treg numbers coincided with rising markers of immune activation (P < 0.0006). The initiation of antiviral therapy significantly increased absolute Treg numbers (P < 0.0031). We find that the expression of CD39, a newly defined ectonucleotidase with immunomodulatory functions on Tregs, correlated with progressive HIV disease, HIV viral load, and immune activation. Of note, when tested in peripheral blood mononuclear cells of healthy volunteers, the in vitro capacity to suppress T-cell proliferation was limited to CD4(+), CD25(high), CD39(+) T cells. Interestingly, Tregs of elite controllers exhibited not only the highest expression of CCR5, CTLA-4, and ICOS but also the lowest level of CD39. The data presented here reconcile the seemingly contradictory results of previous studies looking at Tregs in HIV and highlight the complexity of Treg-mediated immunoregulation during human viral infections.

Mobile phone-assisted basic life support augmented with a metronome.

BACKGROUND: Basic life support (BLS) performed by lay rescuers is poor. We developed software for mobile phones augmented with a metronome to improve BLS. STUDY OBJECTIVES: To assess BLS in lay rescuers with or without software assistance. METHODS: Medically untrained volunteers were randomized to run through a cardiac arrest scenario with ("assisted BLS") or without ("non-assisted BLS") the aid of a BLS software program installed on a mobile phone. RESULTS: Sixty-four lay rescuers were enrolled in the "assisted BLS" and 77 in the "non-assisted BLS" group. The "assisted BLS" when compared to the "non-assisted BLS" group, achieved a higher overall score (19.2 ± 7.5 vs. 12.9 ± 5.7 credits; p < 0.001). Moreover, the "assisted BLS" when compared to the "non-assisted" group checked (64% vs. 27%) and protected themselves more often from environmental risks (70% vs. 39%); this group also called more often for help (56% vs. 27%), opened the upper airway (78% vs. 16%), and had more correct chest compressions rates (44% ± 38% vs. 14% ± 28%; all p < 0.001). However, the "assisted BLS" when compared to the "non-assisted BLS" group, was slower in calling the dispatch center (113.6 ± 86.4 vs. 54.1 ± 45.1 s; p < 0.001) and starting chest compressions (165.3 ± 93.3 vs. 87.1 ± 53.2 s; p < 0.001). CONCLUSIONS: "Assisted BLS" augmented by a metronome resulted in a higher overall score and a better chest compression rate when compared to "non-assisted BLS." However, in the "assisted BLS" group, time to call the dispatch center and to start chest compressions was longer. In both groups, lay persons did not ventilate satisfactorily during this cardiac arrest scenario.

Serum triglycerides and cancer risk in the metabolic syndrome and cancer (Me-Can) collaborative study.

OBJECTIVE: To assess the association between serum triglyceride levels and cancer risk. METHODS: The metabolic syndrome and cancer project (Me-Can) includes cohorts from Norway, Austria, and Sweden; the current study included data on 257,585 men and 256,512 women. The mean age at study entry was 43.8 years for men and 44.2 years for women. The mean follow-up time was 13.4 years (SD = 8.5) for men and 11.9 years (SD = 7.2) for women. Excluding the first year of follow-up, 23,060 men and 15,686 women were diagnosed with cancer. Cox regression models were used to calculate relative risk (RR) of cancer for triglyceride levels in quintiles and as a continuous variable. RRs were corrected for random error by use of regression dilution ratio. RESULTS: Relative risk for top quintile versus bottom quintile of triglycerides of overall cancer was 1.16 (95% confidence interval 1.06-1.26) in men and 1.15 (1.05-1.27) in women. For specific cancers, significant increases for top quintile versus bottom quintile of triglycerides among men were found for cancers of the colon, respiratory tract, the kidney, melanoma and thyroid and among women, for respiratory, cervical, and non-melanoma skin cancers. CONCLUSION: Data from our study provided evidence for a possible role of serum triglycerides in cancer development.

Six-minute walk distance in overweight children and adolescents: effects of a weight-reducing program.

OBJECTIVE: To assess the significance of consecutive six-minute walk tests (6MWTs) during a weight reduction program. STUDY DESIGN: Overweight children and adolescents (n = 113; mean ± standard deviation age, 12.9 ± 2.0 years; 64 girls) performed a standardized 6MWT at the beginning and end of an in-patient weight reduction program consisting of exercise, diet, and educational and psychological support. Their 6-minute walk distance (6MWD) was compared with age- and sex-matched normal-weight children (n = 353). RESULTS: Preintervention 6MWD averaged 93% of control subjects (631 ± 88 m versus 675 ± 70 m, P < .001) and increased significantly to 667 ± 90 m (P < .001) after 27 ± 7 days of intervention (99% of control subjects; P = .260). Participants reduced their body weight from 80.9 ± 19.8 kg to 75.6 ± 19.0 kg, body mass index (BMI) percentile from 98.2 ± 2.1% to 96.8 ± 3.8%, and BMI-standard deviation score from 2.37 ± 0.6 to 2.13 ± 0.6 (P < .001 for each variable). BMI-standard deviation score, height, and the change in heart rate during the 6MWT were significant independent predictors of the 6MWD at preintervention and at post intervention time points (P < .001 each). CONCLUSIONS: The 6MWD increases during a weight reduction program, indicating improvement of physical fitness and decreased metabolic demand during daily activities in overweight children. The 6MWT represents a practical and reliable assessment tool for exercise performance in overweight children and adolescents.

Effects of erythropoietin on frataxin levels and mitochondrial function in Friedreich ataxia--a dose-response trial.

Friedreich ataxia (FRDA) is an autosomal recessive inherited neurodegenerative disorder leading to reduced expression of the mitochondrial protein frataxin. Previous studies showed frataxin upregulation in FRDA following treatment with recombinant human erythropoietin (rhuEPO). Dose-response interactions between frataxin and rhuEPO have not been studied until to date. We administered escalating rhuEPO single doses (5,000, 10,000 and 30,000 IU) in monthly intervals to five adult FRDA patients. Measurements of frataxin, serum erythropoietin levels, iron metabolism and mitochondrial function were carried out. Clinical outcome was assessed using the "Scale for the assessment and rating of ataxia". We found maximal erythropoietin serum concentrations 24 h after rhuEPO application which is comparable to healthy subjects. Frataxin levels increased significantly over 3 months, while ataxia rating did not reveal clinical improvement. All FRDA patients had considerable ferritin decrease. NADH/NAD ratio, an indicator of mitochondrial function, increased following rhuEPO treatment. In addition to frataxin upregulation in response to continuous low-dose rhuEPO application shown in previous studies, our results indicate for a long-lasting frataxin increase after single high-dose rhuEPO administration. To detect frataxin-derived neuroprotective effects resulting in clinically relevant improvement, well-designed studies with extended time frame are required.

Antibody dynamics and spontaneous viral clearance in patients with acute hepatitis C infection in Rio de Janeiro, Brazil.

BACKGROUND: The anti-HCV antibody response has not been well characterized during the early phase of HCV infection and little is known about its relationship to the clinical course during this period. METHODS: We analyzed serial anti-HCV antibodies longitudinally obtained from a prospective cohort of 65 patients with acute HCV infection by using a microparticle enzyme immunoassay AxSYM HCV 3.0 (Abbott Diagnostics) during the first 12 months from HCV acquisition in Rio de Janeiro, Brazil. Spontaneous viral clearance (SVC) was defined as undetectable HCV RNA in serum, in the absence of treatment, for three consecutive HCV PCR tests within 12-months of follow-up. RESULTS: Baseline antibody values were similar among patient groups with self-limiting HCV evolution (n = 34) and persistent viremia (n = 31) [median (interquartile range) signal/cut-off ratio (s/co) 78.7 (60.7-93.8) vs. 93.9 (67.8-111.9), p = 0.26]. During 12-months follow-up, patients with acute spontaneous resolving HCV infection showed significantly lower serial antibody response in comparison to individuals progressing to chronic infection [median (interquartile range) s/co 62.7 (35.2-85.0) vs. 98.4 (70.4-127.4), p < 0.0001]. In addition, patients with self-limiting HCV evolution exhibited an expeditious, sharp decline of serial antibody values after SVC in comparison to those measured before SVC [median (interquartile range) s/co 56.0 (25.4-79.3) vs. 79.4 (66.3-103.0), p < 0.0001]. CONCLUSION: Our findings indicate a rapid short-term decline of antibody values in patients with acute spontaneous resolving HCV infection.

Single shot of alemtuzumab as induction therapy after kidney transplantation is sufficient.

In an earlier study, we were able to show that Tac monotherapy following 2 × 20 mg alemtuzumab induction is at least as effective as Tac-based triple-drug immunosuppression in cadaveric renal transplantation. We were interested to learn whether 1 × 30 mg of alemtuzumab is as effective as 2 × 20 mg. Patients of the initial study group (group A) received 20 mg alemtuzumab on days 0 and 2, and tac monotherapy from day 2 on. This group acted as control group for the new arm (group C), where patients were given only 1 × 30 mg alemtuzumab on day 0 followed by Tac monotherapy from day 2 on with the same target levels as in the control group. Frequency of rejection at 6 months was 15% in the control group compared to 6% in the study group and 20% at 12 months in group A versus 6% in group C (P = 0.034). Time to rejection was 4.9 months in group A and 0.8 in group C. One-year patient survival was 98.5% in both groups, graft survival 96.9% in group A, and 98.5% in group C. Safety profile was similar in both groups apart from more viral and bacterial infections in group C. Single shot alemtuzumab induction of 30 mg is as effective as 2 × 20 mg in cadaveric renal transplantation.

Nutrition of preterm infants in relation to bronchopulmonary dysplasia.

BACKGROUND: The pathogenesis of bronchopulmonary dysplasia (BPD) is multifactorial. In addition to prenatal inflammation, postnatal malnutrition also affects lung development. METHODS: A retrospective study was performed to analyse during the first two weeks of life the total, enteral and parenteral nutrition of premature infants (<31 weeks, birth weight ≤1500 g) born between 08/04 and 12/06. RESULTS: Ninety-five premature infants were analysed: 26 with BPD (27 ± 1 weeks) and 69 without BPD (28 ± 1 weeks). There was no statistical significant difference in the total intake of fluids, calories, glucose or protein and weight gain per day in both groups. The risk of developing BPD was slightly increased in infants with cumulative caloric intake below the minimal requirement of 1230 kcal/kg and a cumulative protein intake below 43.5 g/kg. Furthermore, the risk of developing BPD was significantly higher when infants had a cumulative fluid intake above the recommended 1840 ml/kg. In infants who developed BPD, the enteral nutrition was significantly lower than in non-BPD infants [456 ml/kg (IQR 744, 235) vs. 685 (IQR 987, 511)]. Infants who did not develop BPD reached 50% of total enteral feeding significantly faster [9.6 days vs. 11.5]. CONCLUSIONS: Preterm infants developing BPD received less enteral feeding, even though it was well compensated by the parenteral nutrient supply. Data suggest that a critical minimal amount of enteral feeding is required to prevent development of BPD; however, a large prospective clinical study is needed to prove this assumption.

Single institution experience with the transobturator sling suspension system AdVance® in the treatment of male urinary incontinence: mid-term results.

PURPOSE: To evaluate the clinical outcome after placement of AdVance® sling in men with stress urinary incontinence after prostate surgery. MATERIALS AND METHODS: Incontinence was assessed on basis of number of pad usage. Patients' satisfaction was evaluated using a non-validated patient questionnaire at 12 months post-operatively. RESULTS: Incontinence cure rate (no pad usage) was 61.5% (16/26) and improvement (1-2 pads per day) was seen in 26.9% (7/26). No improvement was observed in 11.5% (3/26) of patients. A total of 87.5% (21/24) of patients were very satisfied with the operation 22 months after surgery. Success rate in patients with prior radiation therapy (20% cure; 40% improvement) was significantly worse. CONCLUSIONS: Placement of the AdVance® sling represents an effective and safe treatment option for patients with post prostate surgery incontinence. Patients that underwent radiotherapy after prostate surgery had lower success rate.

Prospective follow-up of patients with acute hepatitis C virus infection in Brazil.

BACKGROUND: The natural outcome of infection with hepatitis C virus (HCV) varies substantially among individuals. However, little is known about host and viral factors associated with a self-limiting or chronic evolution of HCV infection. METHODS: From 1 January 2001 through 31 December 2008, a consecutive series of 65 patients from Rio de Janeiro, Brazil, with a well-documented diagnosis of acute HCV infection, acquired via various routes, were enrolled in this study. Patients were prospectively followed up for a median of 40 months after the estimated date of HCV infection with serial measurements of serum alanine aminotransferase, HCV RNA, and anti-HCV antibodies. Spontaneous viral clearance (SVC) was defined as undetectable levels of HCV RNA in serum, in the absence of treatment, for 3 consecutive HCV polymerase chain reaction tests within the first 6 months of follow-up. Cox proportional hazards regression was used to identify host and viral predictors of SVC. RESULTS: The cumulative rate of SVC was 44.6% (95% confidence interval, 32.3%-57.5%). Compared with chronic HCV evolution, patients with self-limiting disease had significantly lower peak levels of anti-HCV antibodies (median, 109.0 vs 86.7 optical density-to-cutoff ratio [od/co]; P<.02), experienced disease symptoms more frequently (69.4% vs 100%; P<.001), and had lower viral load at first clinical presentation (median, 4.3 vs 0.0 log copies; P=.01). In multivariate analyses, low peak anti-HCV level (<93.5 od/co) was the only independent predictor for SVC; the hazard ratio compared with high anti-HCV levels (> or =93.5 od/co) was 2.62 (95% confidence interval, 1.11-6.19; P=.03). CONCLUSION: Our data suggest that low levels of anti-HCV antibodies during the acute phase of HCV infection are independently related to spontaneous viral clearance.

Endovascular repair of isolated iliac artery aneurysms.

PURPOSE: To retrospectively evaluate a 12-year experience with endovascular repair of isolated iliac artery aneurysm (IAA). METHODS: From August 1997 through July 2009, 91 patients (81 men; mean age 71 years, range 31-90) underwent endovascular treatment for isolated IAA at our department. Of these, 77 patients received stent-grafts either alone or in combination with coils or an Amplatzer vascular plug (n = 2); 1 patient received a Smart stent combined with coils, and 13 patients were treated with coil embolization only. The aneurysms were classified according to location: type I = common iliac artery (CIA), type II = internal iliac artery (IIA), type III = CIA and IIA, and type IV = external iliac artery with/without CIA and/or IIA involvement. RESULTS: Primary technical success was 90.1% for all aneurysm types and 93.6%, 80%, 88.8%, and 93.3% for types I, II, III, and IV, respectively. Secondary technical success was 96.7% for all types and 97.8%, 95%, 100%, and 93.3%, respectively, for each type. Clinical success was 93.4% for all types and 97.8%, 85%, 100%, and 86.7%, respectively, by type. Complications in 18 (19.8%) patients included 7 type I endoleaks, 3 type II endoleaks, 2 enlarged aneurysm sacs (incomplete embolization), 5 cases of buttock claudication, and 2 stent-graft thromboses. Two patients were converted to open surgery; 10 underwent secondary interventions. Mortality rates were 1.1% (n = 1) at 30 death days and 23.1% (n = 21) over a mean follow-up of 45.9 months (no aneurysm-related death). Cumulative overall survival was 97.7% at 1 year and 47.6% at 10 years. Freedom from aneurysm-related complications was 88.6% at 1 year and 83.5% at 5 years. CONCLUSION: Endovascular repair of isolated IAA is a safe and minimally invasive alternative to surgery. However, it may be associated with several complications and must, therefore, be carefully planned.

Endovascular management of inadvertent subclavian artery catheterization during subclavian vein cannulation.

PURPOSE: To retrospectively review a 9-year experience with endovascular management of inadvertent subclavian artery catheterization during subclavian vein cannulation. MATERIALS AND METHODS: From June 2000 through July 2009 (109 months), 13 patients underwent endovascular management of inadvertent subclavian artery catheterization. All catheters were still in situ, including one 7-F catheter, six 8-F catheters, and six large-bore 10-11-F catheters. Treatment was performed with an Angio-Seal device (n = 6) or balloon catheters (n = 7) and by additional stent-graft placement (n = 4). RESULTS: Mean follow-up was 27.3 months (range, 0.4-78 months). The 30-day mortality rate was 7.7% and the late mortality rate was 46.1%. Primary technical success was achieved in nine patients (69.2%), in four with the use of a compliant balloon catheter and in the other five with an Angio-Seal device. Complications required additional stent-graft placement in four patients (30.8%), one because of stenosis after Angio-Seal device deployment and three as a result of insufficient closure of the puncture site by balloon tamponade. Stent-graft repair was successful in all four patients, for a primary assisted technical success rate of 100%. CONCLUSIONS: Endovascular techniques offer a less invasive alternative to surgery. The present limited experience shows that the use of the Angio-Seal device is not without risks, whereas balloon tamponade is not always reliable in closing the puncture site. Stent-graft placement may be required in patients in whom balloon tamponade fails or in whom the use of the Angio-Seal device is contraindicated.

Analysis of humoral immune responses in rhesus macaques vaccinated with attenuated SIVmac239Deltanef and challenged with pathogenic SIVmac251.

BACKGROUND: To determine the correlation between protection and humoral immune response against simian immunodeficiency virus (SIVmac251), 11 macaques were immunized with live-attenuated SIVmac239Deltanef either intravenously or via the tonsils and exposed to SIVmac251 after either 6 or 15 months along with unvaccinated controls. RESULTS: Independent of the route of vaccine application, viremia was significantly reduced in vaccinees compared with controls 2 weeks post-challenge. Concomitantly, viremia correlated inversely with SIV-specific IgG, complement-mediated lysis and neutralizing antibodies and these parameters seemed to contribute to reduced viremia. During chronic infection, six monkeys controlled viremia in the circulation (two or fewer infectious units per 10(6) PBMCs) and showed no signs of trapping in lymphatic tissues (Appendix S1). CONCLUSIONS: As no significant differences were observed throughout the study, with respect to the humoral immune response and viremia control, between the two vaccinated cohorts, mucosal immunization strategies are recommended due to more simplified application.

Chronic antiepileptic monotherapy, bone metabolism, and body composition in non-institutionalized children.

AIM: The aim of this study was to determine the influence of chronic monotherapy with antiepileptic drugs (AEDs) on vitamin D levels, bone metabolism, and body composition. METHOD: Eighty-five children (38 males, 47 females; mean age 12 y 5 mo, SD 3 y 4 mo) were treated with valproate and 40 children (28 males, 12 females; mean age 11 y 10 mo, SD 3 y) were treated with other AEDs (lamotrigine, sulthiame, or oxcarbazepine), comprising the non-valproate group. Forty-one healthy children (29 males 12 females; mean age 12 y 1 mo, SD 3 y 5 mo) served as a comparison group. Height, weight, body impedance analysis, 25-hydroxyvitamin D, calcium, phosphate, two bone resorption markers (receptor activator of nuclear factor kappaB ligand [RANKL] and tartrate-resistant acid phosphatase 5b [TRAP5b]), osteoprotegerin, and leptin were measured. RESULTS: No child was vitamin D deficient as defined by a 25-hydroxyvitamin D (25OHD) level of less than 25 nmol/l (<10 ng/ml). Leptin, body fat, weight standard deviation score (SDS), and body mass index (BMI) SDS were all significantly higher (each p<0.001) in valproate-treated children than in the non-valproate group, as were calcium (p=0.027) and RANKL (p=0.007) concentrations. Similarly, leptin was significantly higher in the valproate group than in control participants (p<0.001), as were body fat (p=0.023), weight SDS (p=0.046), BMI SDS (p=0.047), calcium (p<0.001), and RANKL (p<0.001), whereas TRAP5b concentrations were significantly lower in the valproate-treated group (p=0.002). Furthermore, calcium and RANKL levels were significantly higher in the non-valproate group than in comparison participants (p<0.001 and p=0.016 respectively). INTERPRETATION: Non-enzyme-inducing or minimal enzyme-inducing AED monotherapy does not cause vitamin D deficiency in otherwise healthy children with epilepsy. Valproate therapy is associated with increases in weight, body fat, and leptin concentration, as well as with a bone metabolic profile that resembles slightly increased parathyroid hormone action.