Low incidence of factor VIII inhibitors in previously untreated patients with severe haemophilia A treated with octanate® : Final report from a prospective study.

INTRODUCTION: Octanate® is a human, plasma-derived, von Willebrand factor-stabilized coagulation factor VIII (FVIII) concentrate with demonstrated haemostatic efficacy in previously treated patients with haemophilia A. AIM: This prospective, open-label study aimed to assess the immunogenicity of octanate® in previously untreated patients (PUPs). METHODS: The study monitored development of FVIII inhibitors in 51 PUPs. Tolerability, viral safety, FVIII recovery and efficacy of octanate® for the prevention and treatment of bleeds and in surgical procedures were also assessed. RESULTS: Five (9.8%) of the 51 patients developed inhibitors during the study, 4 of which (7.8%) were high titre. Three inhibitor cases (5.9%) were considered clinically relevant; 2 were transient inhibitors that disappeared during regular octanate® treatment without a change in dose or treatment frequency. Amongst 45 patients with FVIII:C <1% at baseline and who received ≥20 exposure days (EDs) or had <20 EDs but developed an inhibitor, inhibitor incidence was 11.1% (6.7% clinically relevant). All clinically relevant inhibitors developed within 20 EDs of on-demand treatment. No inhibitors developed in PUPs receiving prophylaxis. All patients who developed inhibitors had either intron 22 inversions or large deletions. Irrespective of the reason for administration, haemostatic efficacy was rated as "excellent" in 99.6% of all infusions (4700 of 4717 infusions), and no complications were reported in 23 surgical procedures. Mean incremental in vivo recovery was 2.0%/IU/kg (±0.7) and 1.9%/IU/kg (±0.5) for the first and second assessments, respectively. Tolerability was rated "very good" in 99.9% of infusions. CONCLUSION: In PUPs with severe haemophilia A, octanate® demonstrated haemostatic efficacy with a low rate of inhibitor development.

ECG-based estimation of dispersion of APD restitution as a tool to stratify sotalol-induced arrhythmic risk.

BACKGROUND: Increased spatial dispersion of restitution properties has been associated to arrhythmic risk. An ECG-based index quantifying restitution dispersion, DRest, is evaluated in patients who experienced Torsades de Pointes (TdP) under sotalol challenge and compared with the response in healthy subjects. METHODS AND RESULTS: ECG recordings were analyzed for quantification of DRest and QTc, among others biomarkers. DRest provides improved discrimination following sotalol administration between TdP and healthy subjects ([min-max]: [0.18-0.22] vs [0.02-0.12]), compared to other biomarkers including QTc ([436-548ms] vs [376-467ms]). Results in healthy subjects are in agreement with simulations of sotalol effects on a human tissue electrophysiological model. CONCLUSIONS: This case study supports the potential of DRest for improved arrhythmia risk stratification even with QTc values below 450ms.

[Ischemia is not an independent predictive factor of chronic renal failure after partial nephrectomy in a solitary kidney in patients without pre-operative renal insufficiency]. / L'ischémie a un impact limité sur la fonction rénale après néphrectomie partielle sur rein unique chez les patients sans insuffisance rénale préopératoire.

OBJECTIVE: To assess the influence of vascular clamping and ischemia time on long-term post-operative renal function following partial nephrectomy (PN) for cancer in a solitary kidney. PATIENTS AND METHODS: This is a retrospective study including 259 patients managed by PN between 1979 and 2010 in 13 centers. Clamping use, technique choice (pedicular or parenchymal clamping), ischemia time, and peri-operative data were collected. Pre-operative and last follow-up glomerular filtration rates were compared. A multivariate analysis using a Cox model was performed to assess the impact of ischemia on post-operative chronic renal failure risk. RESULTS: Mean tumor size was 4.0±2.3cm and mean pre-operative glomerular filtration rate was 60.8±18.9mL/min. One hundred and six patients were managed with warm ischemia (40.9%) and 53 patients with cold ischemia (20.5%). Thirty patients (11.6%) have had a chronic kidney disease. In multivariate analysis, neither vascular clamping (P=0.44) nor warm ischemia time (P=0.1) were associated with a pejorative evolution of renal function. Pre-operative glomerular filtration rate (P<0.0001) and blood loss volume (P=0.02) were significant independent predictive factors of long-term renal failure. CONCLUSION: Renal function following PN in a solitary kidney seems to depend on non-reversible factors such as pre-operative glomerular filtration rate. Our findings minimize the role of vascular clamping and ischemia time, which were not significantly associated with chronic renal failure risk in our study. LEVEL OF EVIDENCE: 5.

Head-to-head comparison of the pharmacokinetic profiles of a high-purity factor IX concentrate (AlphaNine®) and a recombinant factor IX (BeneFIX®) in patients with severe haemophilia B.

Head-on comparative studies of factor IX (FIX) concentrates performed under standardized conditions are rarely conducted regardless of being a valuable instrument guiding health care providers towards better informed and cost-effective decisions. This study is an extension of a multicentre study that assessed the efficacy, safety and pharmacokinetics (PK) of AlphaNine(®) in 25 previously treated patients with severe haemophilia B (FIX:C ≤ 2%). After a washout period ≥ 7 days following the last PK performed with AlphaNine(®) after a dose of 65-75 IU kg(-1) , an identical PK study was performed with BeneFIX(®) on 22 of the same patients. Venous blood samples for analysis were taken at baseline and at 0.25, 0.5, 1, 3, 6, 9, 24, 48, 72 and 74 h post infusion. The outcomes of the comparison of the PK parameters were as follows: Mean (± SD) in vivo recovery (IVR) was 1.3 ± 0.4 IU dL(-1) per IU kg(-1) for AlphaNine(®) and 1.0 ± 0.3 IU dL(-1) per IU kg(-1) for BeneFIX(®) (P < 0.01). Mean terminal half-life, mean residence time, area under the curve, clearance and volume of distribution of BeneFIX(®) were 36.0 ± 12.8 h, 39.3 ± 13.9 h, 1631 ± 467 IU h dL(-1) , 0.046 ± 0.01 dL kg(-1) min(-1) and 1.75 ± 0.52 mL kg(-1) respectively. These values were not significantly different to those observed in AlphaNine(®), although BeneFIX(®) displayed higher than expected IVR values and lower than expected clearance values. In conclusion, AlphaNine(®) showed a comparable half-life, but an IVR significantly higher than that of BeneFIX(®). This dissimilarity may have implications on dosing requirements for on-demand treatment regimes affecting optimal resource allocation.

Results from a large multinational clinical trial (guardian™3) using prophylactic treatment with turoctocog alfa in paediatric patients with severe haemophilia A: safety, efficacy and pharmacokinetics.

Recombinant factor VIII (rFVIII) products provide a safe and efficacious replacement therapy for prophylaxis and treatment of bleeding episodes in patients with severe haemophilia A. This multinational, open-label, non-controlled trial investigated the safety, efficacy and pharmacokinetics (PK) of turoctocog alfa, a new rFVIII product, in a paediatric population. The primary objective was to evaluate safety. A total of 31 younger children (0-5 years) and 32 older children (6-11 years), with ≥ 50 exposure days to any factor VIII (FVIII) product and no history of inhibitors, received prophylaxis with turoctocog alfa (25-50 IU kg(-1) every second day or 25-60 IU kg(-1) three times weekly). PK assessments of turoctocog alfa and the patients' previous FVIII product were performed in 28 patients. Mean exposure to turoctocog alfa was 60 exposure days per patient. This corresponds to approximately 4.5 months in the trial. None of the patients developed inhibitors (≥ 0.6 BU) and no safety concerns were raised. A total of 120 bleeding episodes (95%) were controlled with 1-2 infusions of turoctocog alfa. Based on patient reports, the success rate (defined as 'excellent' or 'good' haemostatic response) for treatment of bleeding episodes was 92%. Overall, the median annualized bleeding rate was 3.0 (interquartile range: 8.5) bleeds patient(-1) year(-1) . PK parameters were comparable between the two age groups. In conclusion, the present large global clinical trial showed that turoctocog alfa was safe, effective in treatment of bleeding episodes and had a prophylactic effect in paediatric patients.

What is the added value of combined core biopsy and fine needle aspiration in the diagnostic process of renal tumours?

PURPOSE: Non-diagnostic results still hinder the routine use of core biopsy (CB) and fine needle aspiration (FNA) in the diagnostic process of renal tumours. Furthermore, substantial interobserver variability has been reported. We assessed the added value of combining the results of CB and FNA by five pathologists in the ex vivo diagnosis of renal mass. METHODS: Two ex vivo core biopsies were taken followed by two FNA passes from extirpated tumours. All samples were evaluated by five blinded pathologists. A consensus diagnosis of the surgical specimen was the index for comparison. For each pathologist, the number of non-diagnostic (non-conclusive or undetermined biology and failed biopsies), correct and incorrect scored cases of each technique was assessed. When a non-diagnostic CB or FNA had a correct diagnostic counterpart, this was considered as of added value. RESULTS: Of the 57 assessed tumours, 53 were malignant. CB was non-diagnostic in 4-10 cases (7-17.5%). FNA established the correct diagnosis in 1-7 of these cases. FNA was non-diagnostic in 2-6 cases (3.5-10.5%), and the counterpart CB established the correct diagnosis in 1-6 of these cases. For the 5 pathologists, accuracy of CB and FNA varied between 82.5-93% and 89.5-96.5%, respectively. Combination of both types of biopsy resulted in 55-57 correct results (accuracy 96.5-100%), i.e., an increase in accuracy of 3.5-14%. CONCLUSION: Combining the result of CB and FNA in renal mass biopsy leads to a higher diagnostic accuracy. Recommendations on which technique used should be adapted to local expertise and logistic possibilities.

The use of mannitol in partial and live donor nephrectomy: an international survey.

PURPOSE: Animal studies have shown the potential benefits of mannitol as renoprotective during warm ischemia; it may have antioxidant and anti-inflammatory properties and is sometimes used during partial nephrectomy (PN) and live donor nephrectomy (LDN). Despite this, a prospective study on mannitol has never been performed. The aim of this study is to document patterns of mannitol use during PN and LDN. MATERIALS AND METHODS: A survey on the use of mannitol during PN and LDN was sent to 92 high surgical volume urological centers. Questions included use of mannitol, indications for use, physician responsible for administration, dosage, timing and other renoprotective measures. RESULTS: Mannitol was used in 78 and 64 % of centers performing PN and LDN, respectively. The indication for use was as antioxidant (21 %), as diuretic (5 %) and as a combination of the two (74 %). For PN, the most common dosages were 12.5 g (30 %) and 25 g (49 %). For LDN, the most common doses were 12.5 g (36.3 %) and 25 g (63.7 %). Overall, 83 % of centers utilized mannitol, and two (percent or centers??) utilized furosemide for renoprotection. CONCLUSIONS: A large majority of high-volume centers performing PN and LDN use mannitol for renoprotection. Since there are no data proving its value nor standardized indication and usage, this survey may provide information for a randomized prospective study.

Clinical efficacy, safety and pharmacokinetic properties of the plasma-derived factor IX concentrate Haemonine in previously treated patients with severe haemophilia B.

Plasma-derived factor IX (FIX) concentrate remains an important choice for replacement therapy in haemophilia B patients. Haemonine is a high purity double-virus inactivated human plasma-derived coagulation FIX concentrate (pdFIX). Aim was to evaluate the clinical efficacy, safety and pharmacokinetic properties of Haemonine in three prospective, open-label uncontrolled studies and a compassionate use program in previously treated patients with severe haemophilia B. Long-term efficacy and safety were investigated in 29 patients treated prophylactically and, in addition, treatment on-demand (TOD) in the case of acute haemorrhage. Pharmacokinetic properties were assessed in 14 patients at baseline and after 3 months of regular treatment. Pharmacokinetic parameters were in accordance with published data and remained nearly unchanged over time, notably recovery and half-life. Mean terminal elimination half-life was 27.6 h and 25.0 h, mean incremental recovery (IU dL(-1) /IU kg(-1)) was 1.55 and 1.60, at baseline and 3 months, respectively. Haemonine was shown to be effective in preventing and controlling bleeds. 55.2% (16/29) of patients were free of bleeds under prophylaxis. 38 haemorrhages occurred, 42% (16/38) required treatment and 87.5% (14/16) resolved after a single infusion, 12.5% after 2 infusions. All responses reported on haemorrhages were rated as 'excellent' or 'good'. Moreover, 'excellent' haemostatic efficacy was demonstrated in 12 surgeries with no complications. Few adverse events (AEs) and no thrombogenic complication, nor induction of FIX inhibitory antibodies were observed. Haemonine is effective, safe and well tolerated in long-term prophylaxis, TOD and when applied after minor and major surgeries.

Low incidence of factor VIII inhibitors in previously untreated patients during prophylaxis, on-demand treatment and surgical procedures, with Octanate®: interim report from an ongoing prospective clinical study.

For patients with haemophilia A (HA), lifelong replacement therapy with factor VIII (FVIII) concentrates is the treatment of choice. Octanate(®) is a plasma-derived, human, von Willebrand factor-stabilized FVIII product with demonstrated haemostatic efficacy in patients with HA. The aim of this ongoing study is to assess the immunogenicity of Octanate(®) in previously untreated patients (PUPs), monitoring for development of FVIII inhibitors. Interim data on 39 PUPs treated for bleeding, prophylactically and for surgical coverage are reported. Two of 39 subjects (5.1%) developed clinically relevant inhibitor titres over the course of the study. Another two displayed inhibitors that disappeared spontaneously without Octanate(®) dose change. All inhibitors developed under on-demand treatment and before exposure day (ED) 50. Remarkably, no inhibitor was observed in PUPs receiving prophylaxis with Octanate(®). Of 39 subjects, 30 had exceeded 50 EDs at the time of this analysis. All inhibitor subjects were found to have large FVIII gene defects, either intron 22-inversions or large deletions. Octanate(®) was well-tolerated and the adverse event profile was consistent with the population studied. The haemostatic efficacy of Octanate(®) in prophylaxis and treatment of bleeding were generally rated as 'excellent', and no complication was reported for surgery. Notable FVIII activity was present in blood at 15 min postadministration, and levels remained high at 1 h. Mean incremental in vivo recovery (IVR) was 2.0 (± 0.6) % IU(-1) kg(-1) . These interim results indicate Octanate(®) to be an efficacious, well-tolerated human FVIII product for management of HA in PUPs, associated with a minimal risk of inhibitors.

A clinical study assessing the pharmacokinetics, efficacy and safety of AlphaNine(®) , a high-purity factor IX concentrate, in patients with severe haemophilia B.

Effective treatment with factor IX (FIX) requires a thorough consideration of the properties of the concentrate to be used as replacement therapy, to date, the only available treatment for haemophilia B. The aim of the study was to determine the pharmacokinetics, clinical efficacy and safety in routine clinical use of AlphaNine(®) , a high-purity human FIX concentrate. This open, single-arm, multicentre, non-randomized trial included 25 subjects (age ≥ 12) with moderate/severe haemophilia B. Pharmacokinetics was assessed at baseline and after a 6-month follow-up. The degree of haemostasis control achieved was evaluated during a 12-month follow-up. Safety was evaluated in terms of tolerance, thrombogenicity, immunogenicity and viral safety. Mean recovery was 1.01 ± 0.19 IU dL(-1) per IU kg(-1) at baseline and 1.23 ± 0.34 IU dL(-1) per IU kg(-1) 6 months later. Terminal half-life was 34.5 ± 6.2 h and 33.7 ± 5.4 h, respectively. Ratios of each parameter between the two pharmacokinetic studies were all close to 1. A total of 1,576,890 IU AlphaNine(®) were administered in 889 infusions (mean dose per infusion: 1774 IU; 3.2 infusions per month per patient). The main reasons for infusion were mild/moderate bleeding (62.3%) and prophylaxis (20.5% continuous, 15.6% intermittent). Overall, 93.0% of the efficacy assessments were rated as excellent/good and 88.8% of bleedings resolved after the first infusion. Twenty-one adverse events were reported in eight patients, none of which was considered related to the study medication. AlphaNine(®) showed a pharmacokinetic profile in agreement with that of other plasma-derived FIX concentrates and provides safe and clinically effective substitution therapy for patients with haemophilia B.

Non-Invasive Identification of Atrial Fibrillation Driver Location Using the 12-lead ECG: Pulmonary Vein Rotors vs. other Locations.

Atrial fibrillation (AF) is an irregular heart rhythm due to disorganized atrial electrical activity, often sustained by rotational drivers called rotors. In the present work, we sought to characterize and discriminate whether simulated single stable rotors are located in the pulmonary veins (PVs) or not, only by using non-invasive signals (i.e., the 12-lead ECG). Several features have been extracted from the signals, such as Hjort descriptors, recurrence quantification analysis (RQA), and principal component analysis. All the extracted features have shown significant discriminatory power, with particular emphasis to the RQA parameters. A decision tree classifier achieved 98.48% accuracy, 83.33% sensitivity, and 100% specificity on simulated data.Clinical Relevance-This study might guide ablation procedures, suggesting doctors to proceed directly in some patients with a pulmonary veins isolation, and avoiding the prior use of an invasive atrial mapping system.

Single-dose (270 microg kg(-1)) recombinant activated factor VII for the treatment and prevention of bleeds in haemophilia A patients with inhibitors: experience from seven European haemophilia centres.

Several studies have suggested that recombinant factor VIIa (rFVIIa) is effective and safe at doses >90 microg kg(-1). In March 2007, the European Medicines Agency approved the use of single-dose rFVIIa 270 microg kg(-1) for the treatment of mild-to-moderate bleeds in haemophilia patients with inhibitors. The aim of this study was to describe the use of single-dose rFVIIa in a real-life setting. In November 2007, seven haemophilia specialists from five European countries convened to share and discuss their experiences with the single-dose rFVIIa regimen within haemophilia A. Case histories of eight patients were discussed in this retrospective study. Six adult and two paediatric patients (age range, 19 months-40 years) were treated with single-dose rFVIIa for a variety of target-joint bleeding, other bleeds and bleeding prevention. Treatment was successful in all the eight cases, with most patients requiring one dose to achieve bleeding resolution. No thrombotic or other safety concerns were raised by single-dose rFVIIa treatment. All patients and physicians preferred single-dose rFVIIa treatment to multiple injections; key benefits of single-dose rFVIIa treatment reported by patients and physicians included improved quality of life, greater convenience and ease of administration, improved compliance, faster control of bleeding, less injection-related pain and faster pain relief. In the patients reported here, single-dose rFVIIa 270 microg kg(-1) appears to be an effective and safe haemostatic treatment that improves the quality of life and convenience of treatment for patients. Such treatment might be of particular benefit for patients with difficult venous access or needle phobia.

Efficacy and safety of OCTANINE F in children with haemophilia B.

OCTANINE F is a high-purity blood clotting factor IX concentrate that has been shown to be effective and safe in adults with haemophilia B. At present, there are no prospective clinical study data on FIX replacement therapy in young children. The primary objective of this trial was to investigate the immunogenicity of OCTANINE F in children aged <6 years with haemophilia B. Secondary objectives were to assess the efficacy, viral safety and tolerability of OCTANINE F in this patient population. Twenty-five children aged <6 years with moderate or severe haemophilia B, including six who were previously untreated and 13 who had less than previous 50 exposure days were assigned to prophylactic or on-demand treatment with OCTANINE F over a 12- to 24-month period. Immunogenicity was assessed at baseline, during the treatment period and at the end of treatment by monitoring the levels of inhibitor. OCTANINE F was not associated with the development of an inhibitor in any patient during the study; all patients had a FIX inhibitor level of <0.4 Bethesda units (BU) for all samples taken throughout the study. The efficacy of OCTANINE F was rated as excellent in 96.4% of 499 bleeding episodes and tolerability was rated as very good in 97% of 1684 injections. OCTANINE F was shown to be effective and well tolerated in children aged <6 years with moderate or severe haemophilia B, including previously untreated patients, with no reported cases of FIX inhibitors or thrombotic events.

[Laparoscopic pelvic surgery: Where do we stand in the year 2006?]. / Laparoskopische Beckenchirurgie: Wo stehen wir im Jahr 2006?

Laparoscopic radical prostatectomy has become an equivalent alternative to the open retropubic approach, offering the advantages of minimally invasive surgery. It is being applied increasingly in Germany and the rest of Europe. Whether the surgical robot da Vinci will be used for this procedure to the same extent as in the United States is unpredictable because of high investment and maintenance costs. Similarly, laparoscopic sacrocolpopexy has proven to be a viable option compared to open transabdominal or transvaginal surgery, showing a significant reduction in postoperative morbidity. The value of radical cystectomy is controversial despite proven feasability. On one hand, the technical difficulties of purely laparoscopic urinary diversion result in very long operating times, and in the case of the laparoscopically assisted creation of a neobladder, the advantage of this approach has to be questioned. On the other hand, a maximum rate of 30% of local recurrences and distant metastases indicates at least poor patient selection. In conclusion, this procedure should be limited to a few experienced centers.

Evaluation of T-wave alternans activity under stress conditions after 5 d and 21 d of sedentary head-down bed rest.

It is well known that prolonged microgravity leads to cardiovascular deconditioning, inducing significant changes in autonomic control of the cardiovascular system. This may adversely influence cardiac repolarization, and provoke cardiac rhythm disturbances. T-wave alternans (TWA), reflecting temporal and spatial repolarization heterogeneity, could be affected. The aim of this work was to test the hypothesis that 5 d and 21 d head-down (-6°) bed rest (HDBR) increases TWA, thus suggesting a higher underlying electrical instability and related arrhythmogenic risk. Forty-four healthy male volunteers were enrolled in the experiments as part of the European Space Agency's HDBR studies. High-fidelity ECG was recorded during orthostatic tolerance (OT) and aerobic power (AP) tests, before (PRE) and after HDBR (POST). A multilead scheme for TWA amplitude estimation was used, where non-normalized and T-wave amplitude normalized TWA indices were computed. In addition, spectral analysis of heart rate variability during OT was assessed. Both 5 d and 21 d HDBR induced a reduction in orthostatic tolerance time (OTT), as well as a decrease in maximal oxygen uptake and reserve capacity, thus suggesting cardiovascular deconditioning. However, TWA indices were found not to increase. Interestingly, subjects with lower OTT after 5 d HDBR also showed higher TWA during recovery after OT testing, associated with unbalanced sympathovagal response, even before the HDBR. In contrast with previous observations, augmented ventricular heterogeneity related to 5 d and 21 d HDBR was not sufficient to increase TWA under stress conditions.