Pharmacokinetics of trastuzumab emtansine (T-DM1) as a single agent or in combination with pertuzumab in HER2-positive breast cancer patients with recurrent or locally advanced metastatic breast cancer.

PURPOSE: The phase III MARIANNE study investigated single-agent trastuzumab emtansine (T-DM1) and combination T-DM1 plus pertuzumab as the first-line treatment for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). Pharmacokinetic properties of T-DM1 and pertuzumab in these patients and the potential for drug-drug interactions (DDIs) were assessed. METHODS: Pharmacokinetic samples of T-DM1-related analytes (T-DM1 conjugate, total trastuzumab, DM1) and pertuzumab were analyzed. Observed pharmacokinetic data were summarized for all analytes. Historical population pharmacokinetic models for T-DM1 conjugate and pertuzumab in HER2-positive MBC were used to derive empirical Bayes estimates of pharmacokinetic parameters. RESULTS: In MARIANNE (N = 375), mean ± standard deviation population pharmacokinetic model-predicted Cycle 1 Cmax for T-DM1 conjugate was 74.4 ± 10.1 µg/mL, Cycle 1 Ctrough was 1.34 ± 0.802 µg/mL, and area under the concentration-time curve from time zero to infinity after first dose (AUCinf) was 338 ± 69.5 µg*day/mL. These values were similar to other T-DM1 studies. Pharmacokinetics of T-DM1 conjugate and other analytes (total trastuzumab, DM1) were similar with or without pertuzumab. In the pertuzumab plus T-DM1 arm, mean model-predicted Cycle 1 pertuzumab Cmax, Ctrough, and AUCinf were 276 ± 50.0 µg/mL, 64.8 ± 17.9 µg/mL, and 4470 ± 1360 µg*day/mL, respectively. These values were similar to other pertuzumab studies. CONCLUSIONS: Based on the population pharmacokinetic analysis of T-DM1 conjugate and pertuzumab, pharmacokinetics are similar across different lines of treatment and stages of disease including previously untreated MBC patients, and no DDIs were identified for combined use of T-DM1 and pertuzumab.

Exposure-response analyses of trastuzumab emtansine in patients with HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane.

PURPOSE: In the phase III EMILIA study, trastuzumab emtansine (T-DM1) significantly improved progression-free survival (PFS) and overall survival (OS) versus capecitabine plus lapatinib (control) in previously treated human epidermal growth factor receptor 2-positive advanced breast cancer. Using EMILIA data, we evaluated the T-DM1 exposure-response relationship. METHODS: Exposure-response relationships were examined with four exposure metrics [model-predicted and observed minimum concentration (C min) and area under the concentration-time curve from time zero to day 21 of T-DM1 at cycle 1] and multiple efficacy (OS, PFS, objective response rate) and safety (grade ≥ 3 adverse events, grade ≥ 3 thrombocytopenia, grade ≥ 3 hepatotoxicity) endpoints. RESULTS: An apparent exposure-response trend was observed between model-predicted exposure metrics and efficacy; trends for observed exposure metrics were shallower and often not significant. Although median OS and PFS were numerically longer in patients with higher versus lower model-predicted cycle 1 C min, OS and PFS hazard ratios for T-DM1-treated patients in the lowest exposure quartile (Q1) versus control were < 1 after adjusting for baseline risk factors (e.g., ECOG status, tumor burden, measurable disease, and number of disease sites). No meaningful exposure-response relationship was observed for any safety endpoints. CONCLUSION: Exposure-response relationships for efficacy were inconsistent across exposure metrics; model-predicted cycle 1 C min showed the strongest exposure-response trend. The Q1 subgroup based on model-predicted cycle 1 C min had numerically similar or better OS and PFS versus control following covariate adjustment. The approved T-DM1 dose (3.6 mg/kg every 3 weeks) has a positive benefit-risk ratio versus control, even for the T-DM1 Q1 subgroup.

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.

Trastuzumab Emtansine With or Without Pertuzumab Versus Trastuzumab Plus Taxane for Human Epidermal Growth Factor Receptor 2-Positive, Advanced Breast Cancer: Primary Results From the Phase III MARIANNE Study.

Purpose Trastuzumab and pertuzumab are human epidermal growth factor receptor 2 (HER2) -targeted monoclonal antibodies, and trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that combines the properties of trastuzumab with the cytotoxic activity of DM1. T-DM1 demonstrated encouraging efficacy and safety in a phase II study of patients with previously untreated HER2-positive metastatic breast cancer. Combination T-DM1 and pertuzumab showed synergistic activity in cell culture models and had an acceptable safety profile in a phase Ib and II study. Methods In the MARIANNE study, 1,095 patients with centrally assessed, HER2-positive, advanced breast cancer and no prior therapy for advanced disease were randomly assigned 1:1:1 to control (trastuzumab plus taxane), T-DM1 plus placebo, hereafter T-DM1, or T-DM1 plus pertuzumab at standard doses. Primary end point was progression-free survival (PFS), as assessed by independent review. Results T-DM1 and T-DM1 plus pertuzumab showed noninferior PFS compared with trastuzumab plus taxane (median PFS: 13.7 months with trastuzumab plus taxane, 14.1 months with T-DM1, and 15.2 months with T-DM1 plus pertuzumab). Neither experimental arm showed PFS superiority to trastuzumab plus taxane. Response rate was 67.9% in patients who were treated with trastuzumab plus taxane, 59.7% with T-DM1, and 64.2% with T-DM1 plus pertuzumab; median response duration was 12.5 months, 20.7 months, and 21.2 months, respectively. The incidence of grade ≥ 3 adverse events was numerically higher in the control arm (54.1%) versus the T-DM1 arm (45.4%) and T-DM1 plus pertuzumab arm (46.2%). Numerically fewer patients discontinued treatment because of adverse events in the T-DM1 arms, and health-related quality of life was maintained for longer in the T-DM1 arms. Conclusion T-DM1 showed noninferior, but not superior, efficacy and better tolerability than did taxane plus trastuzumab for first-line treatment of HER2-positive, advanced breast cancer.

A Phase I Pharmacokinetic Study of Trastuzumab Emtansine (T-DM1) in Patients with Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer and Normal or Reduced Hepatic Function.

OBJECTIVE: The aim of this study was to evaluate the pharmacokinetics (PK) of trastuzumab emtansine (T-DM1) and relevant analytes in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer and hepatic impairment. METHODS: Patients were enrolled in three independent parallel cohorts based on hepatic function per Child-Pugh criteria: normal hepatic function, mild hepatic impairment, and moderate hepatic impairment. Patients received T-DM1 3.6 mg/kg intravenously every 3 weeks. PK samples were collected during cycles 1 and 3, and the PK of T-DM1 and relevant analytes were characterized and compared across cohorts. RESULTS: Compared with patients with normal hepatic function (n = 10), T-DM1 clearance at cycle 1 was 1.8- and 4.0-fold faster in the mild (n = 10) and moderate (n = 8) cohorts, respectively. The trend of faster clearance was less apparent in cycle 3, with similar T-DM1 clearance across cohorts (mean ± standard deviation 8.16 ± 3.27 [n = 9], 9.74 ± 3.62 [n = 7], and 8.99 and 10.2 [individual values, n = 2] mL/day/kg for the normal, mild, and moderate cohorts, respectively). T-DM1 clearance at cycle 1 correlated significantly with baseline albumin, aspartate aminotransferase, and HER2 extracellular domain concentrations (p < 0.05). Plasma concentrations of DM1 and DM1-containing catabolites were low and were comparable across cohorts. CONCLUSIONS: No increase in systemic DM1 concentration was observed in patients with mild or moderate hepatic impairment versus those with normal hepatic function. The faster T-DM1 clearance observed at cycle 1 in patients with hepatic impairment appeared to be transient. After repeated dosing (three cycles), T-DM1 exposure in patients with mild and moderate hepatic impairment was within the range seen in those with normal hepatic function.

Ethnic sensitivity assessment of the antibody-drug conjugate trastuzumab emtansine (T-DM1) in patients with HER2-positive locally advanced or metastatic breast cancer.

PURPOSE: Trastuzumab emtansine (T-DM1) is indicated for previously treated HER2-positive metastatic breast cancer. Ethnic sensitivity assessment of T-DM1 was conducted using data from eight clinical studies to ensure that the clinically recommended dose is appropriate across ethnicities. METHODS: Four approaches were used: (1) non-compartmental analysis (NCA) comparing pharmacokinetic parameters of T-DM1 and relevant analytes across ethnic groups, (2) population pharmacokinetic (popPK) analysis assessing the impact of ethnicity on pharmacokinetics, (3) comparison of T-DM1 pharmacokinetics in Japanese patients versus the global population, and (4) exposure-response analyses assessing the impact of ethnicity on safety and efficacy. RESULTS: NCA pharmacokinetic parameters (T-DM1, total trastuzumab, DM1) were comparable across ethnic groups; mean cycle 1 T-DM1 AUCinf was 475, 442, and 518 day µg/mL for white (n = 461), Asian (n = 68), and others (n = 57), respectively. PopPK analysis showed that ethnicity (white, Asian, and others) was not a significant covariate for T-DM1 pharmacokinetics (n = 671). Additionally, visual predictive check plots indicated that observed pharmacokinetic profiles in Japanese patients (n = 42) were within the prediction interval generated from the final PopPK model. Exposure-response analyses showed that ethnicity was not a significant covariate impacting efficacy or hepatotoxicity risk, but there was a trend of greater thrombocytopenia risk among Asians versus non-Asians, which could not be explained by similar exposure between the ethnic groups. Most Asians with thrombocytopenia were able to continue T-DM1 using dose-adjustment rules recommended for the global population. CONCLUSIONS: These results suggest that T-DM1 pharmacokinetics are comparable across ethnic groups and that use of the current dosing regimen is appropriate across ethnicities.

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.

The exclusive use of coagulation factor concentrates enables reversal of coagulopathy and decreases transfusion rates in patients with major blunt trauma.

BACKGROUND: FFP and coagulation factor concentrates are used to correct trauma-induced coagulopathy (TIC). However, data on coagulation profiles investigating effects of therapy are scarce. METHODS: This is an analysis of 144 patients with major blunt trauma ((ISS)≥15), who were enrolled in a prospective cohort study investigating characteristics and treatment of TIC. Patients who received fibrinogen concentrate and/or prothrombin complex concentrate alone (CF Group) were compared with those additionally receiving FFP transfusions (FFP Group). RESULTS: Sixty-six patients exclusively received CF, while 78 patients additionally received FFP. Overall, patients were comparable regarding age, gender and ISS (CF Group, ISS 37 (29, 50); FFP Group ISS 38 (33, 55), p=0.28). Patients treated with CF alone showed sufficient haemostasis and received significantly fewer units of red blood cells (RBC) and platelets than did those also receiving FFP [(RBC 2(0, 4) U vs. 9 (5, 12) U; platelets 0 (0, 0) U vs. 1 (0, 2) U, p<0.001)]. In addition, fewer patients in the CF Group developed multiorgan failure (MOF) (18.2% vs. 37.2%, p=0.01) or sepsis (16.9% vs. 35.9%, p=0.014) than in the FFP Group. Propensity score-matching (n=28 pairs) used to reduce the impact of treatment selection confirmed that additional FFP administration showed no benefit in restoring haemostasis, but was associated with significantly higher transfusion rates for RBC and platelets. CONCLUSION: The use of CF alone effectively corrected coagulopathy in patients with severe blunt trauma and concomitantly decreased exposure to allogeneic transfusion, which may translate into improved outcome.

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.

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.

Elevated γ-glutamyltransferase in implantable cardioverter defibrillator patients.

BACKGROUND: Elevated γ-glutamyltransferase (GGT) is a new risk factor for cardiovascular diseases, but its impact on ventricular tachyarrhythmia occurrence and survival in patients with an implantable cardioverter defibrillator (ICD) is unknown. METHODS AND RESULTS: Considering that GGT levels are gender-dependent, female ICD recipients were excluded from our database because of the low incidence of events. In a retrospective analysis, appropriate ICD therapy (both shocks and antitachycardia pacing due to ventricular tachyarrhythmias) occurred in 31.9% of 320 male patients who had received an ICD for primary prevention (median follow-up of 2.3 years), and in 55.1% of 423 male patients who had received an ICD for secondary prevention (median follow-up of 3.9 years). Compared to normal low GGT plasma levels (below 28 U/L), total mortality but not risk for appropriate ICD therapy was elevated for higher GGT categories (p for trend = 0.004 in primary prevention and p for trend = 0.002 in secondary prevention, respectively). In Cox regression analysis, elevated GGT (>56 U/L) remained an independent predictor of death both in primary (p = 0.011) and in secondary prevention (p = 0.006). Patients with elevated GGT and renal insufficiency defined by an estimated glomerular filtration rate <60 ml/min/1.73 m(2) suffered from excess total mortality jeopardizing the benefit of ICD therapy. CONCLUSION: Elevation of GGT is an important adverse prognostic parameter in ICD patients. A possible role of GGT for improved patient selection for ICD therapy deserves further investigation.

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.

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.

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 percent (16/26) and improvement (1-2 pads per day) was seen in 26.9 percent (7/26). No improvement was observed in 11.5 percent (3/26) of patients. A total of 87.5 percent (21/24) of patients were very satisfied with the operation 22 months after surgery. Success rate in patients with prior radiation therapy (20 percent cure; 40 percent 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.

Duration of the A(H)-A(Md) interval predicts occurrence of AV-block after radiofrequency ablation of the slow pathway.

PURPOSE: Modification of the slow pathway (SP) of the atrio-ventricular node by radiofrequency ablation is the most effective treatment to cure AV nodal reentry tachycardia (AVNRT). However, this therapy may be complicated by AV-block (AVB). We sought to evaluate the predictive value of the A(H)-A(Md) interval-the electrical delay between atrial signals on the His- and the ablation-catheter-upon development of AVB during SP ablation. METHODS: The associations between A(H)-A(Md) interval, occurrence of ventriculo-atrial block (VAB) during junctional activity (JA) and transient or permanent AVB were analyzed retrospectively for 1585 RF applications at the SP in 393 patients diagnosed with AVNRT. The value of A(H)-A(Md) was further tested prospectively in 118 AVNRT patients, who were only ablated at targets with intervals >20 ms. RESULTS: Forty-six RF deliveries resulted in transient or permanent AV-conduction disturbances. Shorter A(H)-A(Md) intervals were associated with the occurrence of VAB during JA (p < 0.001) and AVB (p < 0.001). A(H)-A(Md) was the strongest predictor for VAB or AVB in multivariate regression analyses, followed by the radiological distance between the catheters. In the prospective study, permanent high-degree AVB was not observed when the A(H)-A(Md) at the ablation site was >20 ms. CONCLUSION: The A(H)-A(Md) interval is a better predictor for occurrence of conduction block during ablation for AVNRT than the radiological distance between the His- and the ablation-catheter. The risk of permanent AVB can be minimized, if only sites with an A(H)-A(Md) longer than 20 ms are targeted for ablation.

Appropriate therapy but not inappropriate shocks predict survival in implantable cardioverter defibrillator patients.

BACKGROUND: Inappropriate implantable cardioverter defibrillator (ICD) shocks have been linked to a worse clinical outcome due to direct myocardial injury. HYPOTHESIS: The occurrence of ventricular tachyarrhythmia indicating progression of the underlying heart disease, but not the ICD shock itself, has prognostic impact in clinical routine. METHODS: In a retrospective study, 1117 recipients of an ICD were analyzed with respect to appropriate and inappropriate therapies and survival. RESULTS: During a mean follow-up of 2.92 years, appropriate therapy occurred in 27.7% and 54.0% of patients who had received an ICD for primary and secondary prevention of sudden cardiac death (SCD), respectively (P<0.0001). Inappropriate shock therapy occurred in 15.0% and 25.4% of patients who had received an ICD for primary and secondary prevention of SCD, respectively (P = 0.122). Appropriate ICD therapy had a strong impact on overall survival (P<0.0001), and this association was found both in primary (P<0.0001) and secondary (P = 0.002) prevention of SCD. Inappropriate ICD shocks had no impact on total mortality, neither in primary nor secondary prevention of SCD. CONCLUSIONS: Inappropriate shocks do not affect survival, in strong contrast to appropriate ICD therapy. Our study does not support the hypothesis that shock therapy in itself worsens clinical outcome. However, it confirms that appropriate ICD therapy is a warning sign and should prompt physicians to consider additional treatment strategies.

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.