Filter feeders are key to small microplastic residence times in stratified lakes: A virtual experiment.

Microplastic (MP) is potentially harmful to lake ecosystems, with its uptake into the food web largely controlled by its residence time in the lake water column. Here we combine laboratory and virtual experiments to quantify residence times of small MP (<15 µm) in two contrasting model lakes; Lake Constance (large lake) and Esthwaite Water (a small lake). We compare MP residence times in a purely physical system with MP transport controlled by sinking and mixing to a model where, in addition to physical processes, zooplankton package MP into faecal pellets that are then egested into the water column. The laboratory experiments showed that MP settling velocities increased from ~5 × 10-6-10-3 mm s-1 for pristine MP to ~1 mm s-1 for MP embedded faeces. Modeled lake residence times for the 0.5 and 5 µm particles were >15 years in the abiotic models, while in the biotic simulations they were reduced to ~1 year. There was little difference between abiotic and biotic simulations for the 15 µm particles. The ratio of the MP zooplankton uptake velocity to the sinking velocity (v_up/vs_epi) was used to classify biological vs. physical transport pathways. For the 0.5 and 5 µm particles v_up/vs_epi was ≫1 in all cases for both lakes, while for the 15 µm MP there was a transition between biological and physical processes dominating residence times depending on zooplankton numbers. Our results suggest that packaging of small MP in faecal pellets by zooplankton will control its residence time in lakes. Moreover, the majority of small MP will cycle through organisms before reaching the sediment, increasing the likelihood of negative ecological effects and transfer in the food web.

Extended induction chemotherapy does not improve the outcome for high-risk neuroblastoma patients: results of the randomized open-label GPOH trial NB2004-HR.

BACKGROUND: Long-term survival of high-risk neuroblastoma patients is still below 50% despite intensive multimodal treatment. This trial aimed to address whether the addition of two topotecan-containing chemotherapy courses compared to standard induction therapy improves event-free survival (EFS) of these patients. PATIENTS AND METHODS: An open-label, multicenter, prospective randomized controlled trial was carried out at 58 hospitals in Germany and Switzerland. Patients aged 1-21 years with stage 4 neuroblastoma and patients aged 6 months to 21 years with MYCN-amplified tumors were eligible. The primary endpoint was EFS. Patients were randomly assigned to standard induction therapy with six chemotherapy courses or to experimental induction chemotherapy starting with two additional courses of topotecan, cyclophosphamide, and etoposide followed by standard induction chemotherapy (eight courses in total). After induction chemotherapy, all patients received high-dose chemotherapy with autologous hematopoietic stem cell rescue and isotretinoin for consolidation. Radiotherapy was applied to patients with active tumors at the end of induction chemotherapy. RESULTS: Of 536 patients enrolled in the trial, 422 were randomly assigned to the control arm (n = 211) and the experimental arm (n = 211); the median follow-up time was 3.32 years (interquartile range 1.65-5.92). At data lock, the 3-year EFS of experimental and control patients was 34% and 32% [95% confidence Interval (CI) 28% to 40% and 26% to 38%; P = 0.258], respectively. Similarly, the 3-year overall survival of the patients did not differ [54% and 48% (95% CI 46% to 62% and 40% to 56%), respectively; P = 0.558]. The response to induction chemotherapy was not different between the arms. The median number of non-fatal toxicities per patient was higher in the experimental group while the median number of toxicities per chemotherapy course was not different. CONCLUSION: While the burden for the patients was increased by prolonging the induction chemotherapy and the toxicity, the addition of two topotecan-containing chemotherapy courses did not improve the EFS of high-risk neuroblastoma patients and thus cannot be recommended. CLINICAL TRIALS. GOV NUMBER: NCT number 03042429.

Quality assurance in CT: implementation of the updated national diagnostic reference levels using an automated CT dose monitoring system.

AIM: To evaluate the implementation of the updated computed tomography (CT) diagnostic reference levels (DRLs) from the German Federal Office for Radiation Protection into clinical routine using an automatic CT dose monitoring system. METHODS AND MATERIALS: CT radiation exposure was analysed before and after implementing the updated national DRLs into routine clinical work in 2016. After the implementation process, institutional CT protocols were mapped to the anatomical regions for which DRLs were provided. Systematically, protocols that exceeded the thresholds were optimised and analysed in detail. The CT radiation output parameters analysed were volumetric CT dose index (CTDIvol) and dose-length product (DLP). Three radiologists evaluated subjective image quality using a three-point Likert scale. RESULTS: The study included 94,258 CT series (from 27,103 CT examinations) in adult patients performed in 2016. When averaged over all body regions with available DRL, institutional CTDIvol/DLP values were always below the DRLs (65.2±32.9%/67.3±41.5% initially; 59.4±32%/60.5±39.9% after optimisation). Values exceeding the national DRLs were found for pelvis (n=268; CTDIvol 107.7±65.7%/DLP 106.3±79.3%), lumbar spine (n=91; 160.8±74.7%/175.2±104.1%), and facial bones (n=527; 108±39%/152.7±75.7%). After optimisation, CTDIvol and DLP were 87.9±73%/87.8±80.8% for the pelvis, 67.8±33.2%/74.5±50.6% for the lumbar spine and 95.1±45.8%/133.3±74.6% for the viscerocranium. CONCLUSION: An automatic CT dose monitoring system enabled not only comprehensive monitoring of a DRL implementation process but can also help to optimise radiation exposure.

Iterative metal artefact reduction in CT: can dedicated algorithms improve image quality after spinal instrumentation?

AIM: To investigate the value of dedicated computed tomography (CT) iterative metal artefact reduction (iMAR) algorithms in patients after spinal instrumentation. MATERIALS AND METHODS: Post-surgical spinal CT images of 24 patients performed between March 2015 and July 2016 were retrospectively included. Images were reconstructed with standard weighted filtered back projection (WFBP) and with two dedicated iMAR algorithms (iMAR-Algo1, adjusted to spinal instrumentations and iMAR-Algo2, adjusted to large metallic hip implants) using a medium smooth kernel (B30f) and a sharp kernel (B70f). Frequencies of density changes were quantified to assess objective image quality. Image quality was rated subjectively by evaluating the visibility of critical anatomical structures including the central canal, the spinal cord, neural foramina, and vertebral bone. RESULTS: Both iMAR algorithms significantly reduced artefacts from metal compared with WFBP (p<0.0001). Results of subjective image analysis showed that both iMAR algorithms led to an improvement in visualisation of soft-tissue structures (median iMAR-Algo1=3; interquartile range [IQR]:1.5-3; iMAR-Algo2=4; IQR: 3.5-4) and bone structures (iMAR-Algo1=3; IQR:3-4; iMAR-Algo2=4; IQR:4-5) compared to WFBP (soft tissue: median 2; IQR: 0.5-2 and bone structures: median 2; IQR: 1-3; p<0.0001). Compared with iMAR-Algo1, objective artefact reduction and subjective visualisation of soft-tissue and bone structures were improved with iMAR-Algo2 (p<0.0001). CONCLUSION: Both iMAR algorithms reduced artefacts compared with WFBP, however, the iMAR algorithm with dedicated settings for large metallic implants was superior to the algorithm specifically adjusted to spinal implants.

Facet tropism and facet joint orientation: risk factors for the development of early biochemical alterations of lumbar intervertebral discs.

OBJECTIVE: To assess the glycosaminoglycan (GAG) content of lumbar intervertebral discs (IVD) in healthy volunteers with facet tropism (FT) and sagittal facet joint (FJ) orientation using glycosaminoglycan chemical exchange saturation transfer imaging (gagCEST). METHOD: Seventy-five lumbar IVDs of twenty-five young, healthy volunteers without any history of lumbar spine pathologies (13 female; 12 male; mean age: 28.0 ± 4.4 years; range: 21-35 years) were examined with a 3T MRI scanner. Orientation of FT and FJ were assessed for L3/4, L4/5 and L5/S1 using standard T2 weighted images. Biochemical gagCEST imaging was used to determine the GAG content of each nucleus pulposus (NP) and annulus fibrosus (AF). RESULTS: Significantly higher gagCEST values of NP were found in volunteers without FT and normal FJ orientation compared to volunteers with FT and sagittal FJ orientation >45° (P < 0.0001). GagCEST values were significantly higher in volunteers without FT compared to volunteers with moderate or severe FT (moderate FT: P < 0.0001; severe FT: P = 0.0033). Volunteers with normal FJ orientation showed significantly higher gagCEST values compared to those with sagittal FJ orientation >45° (P < 0.001). We found a significant, negative correlation between gagCEST values and higher angels in sagittal FJ orientation (rho = -0.459; P < 0.0001). CONCLUSION: GagCEST analysis indicated lower GAG values of NP in young volunteers with FT and sagittal orientated FJ, indicating that FT and sagittal orientation of the FJ represent risk factors for the development of early biochemical alterations of lumbar IVDs.

Dose Monitoring in Radiology Departments: Status Quo and Future Perspectives.

UNLABELLED: The number of computed tomography examinations has continuously increased over the last decades and accounts for a major part of the collective radiation dose from medical investigations. For purposes of quality assurance in modern radiology a systematic monitoring and analysis of dose related data from radiological examinations is mandatory. Various ways of collecting dose data are available today, for example the Digital Imaging and Communication in Medicine - Structured Report (DICOM-SR), optical character recognition and DICOM-modality performed procedure steps (MPPS). The DICOM-SR is part of the DICOM-standard and provides the DICOM-Radiation Dose Structured Report, which is an easily applicable and comprehensive solution to collect radiation dose parameters. This standard simplifies the process of data collection and enables comprehensive dose monitoring. Various commercial dose monitoring software devices with varying characteristics are available today. In this article, we discuss legal obligations, various ways to monitor dose data, current dose monitoring software solutions and future perspectives in regard to the EU Council Directive 2013/59/EURATOM. KEY POINTS: • Automated, systematic dose monitoring is an important element in quality assurance of radiology departments. • DICOM-RDSR-capable CT scanners facilitate the monitoring of dose data. • A variety of commercial and non-commercial dose monitoring software tools are available today. • Successful dose monitoring requires comprehensive infrastructure for monitoring, analysing and optimizing radiation exposure. Citation Format: • Boos J, Meineke A, Bethge OT et al. Dose Monitoring in Radiology Departments: Status Quo and Future Perspectives. Fortschr Röntgenstr 2016; 188: 443 - 450.

Asymmetrical flow field-flow fractionation for the analysis of PEG-asparaginase.

Monomethoxypolyethylene glycol L-asparaginase (PEG-ASNASE) is the PEGylated version of the enzyme L-asparaginase (ASNASE). Both are used for remission induction in acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL). The treatment control is generally carried out by performing activity assays, though methods to determine the actual enzyme rather than its activity are rare. Using asymmetrical flow field-flow fractionation (AF4) offered the chance to develop a method capable of simultaneously measuring PEG-ASNASE and PEG. A method validation was performed in accordance with FDA guidelines for PEG-ASNASE from non-biological solutions. The method unfolded a linearity of 15-750 U/mL with coefficients of correlation of r(2)>0.99. The coefficients of variation (CV) for within-run and between-run variability were 1.18-10.15% and 2.43-8.73%, respectively. Furthermore, the method was used to perform stability tests of the product Oncaspar® (PEG-ASNASE) and estimation of the molecular weight by multi-angle light scattering (MALS) of stressed samples to correlate them with the corresponding activity. The findings indicate that Oncaspar® stock solution should not be stored any longer than 24 h at room temperature and cannot be frozen in pure aqueous media. The validated method might be useful for the pharmaceutical industry and its quality control of PEG-ASNASE production.

Cloud-Based CT Dose Monitoring using the DICOM-Structured Report: Fully Automated Analysis in Regard to National Diagnostic Reference Levels.

PURPOSE: To implement automated CT dose data monitoring using the DICOM-Structured Report (DICOM-SR) in order to monitor dose-related CT data in regard to national diagnostic reference levels (DRLs). MATERIALS AND METHODS: We used a novel in-house co-developed software tool based on the DICOM-SR to automatically monitor dose-related data from CT examinations. The DICOM-SR for each CT examination performed between 09/2011 and 03/2015 was automatically anonymized and sent from the CT scanners to a cloud server. Data was automatically analyzed in accordance with body region, patient age and corresponding DRL for volumetric computed tomography dose index (CTDIvol) and dose length product (DLP). RESULTS: Data of 36,523 examinations (131,527 scan series) performed on three different CT scanners and one PET/CT were analyzed. The overall mean CTDIvol and DLP were 51.3% and 52.8% of the national DRLs, respectively. CTDIvol and DLP reached 43.8% and 43.1% for abdominal CT (n=10,590), 66.6% and 69.6% for cranial CT (n=16,098) and 37.8% and 44.0% for chest CT (n=10,387) of the compared national DRLs, respectively. Overall, the CTDIvol exceeded national DRLs in 1.9% of the examinations, while the DLP exceeded national DRLs in 2.9% of the examinations. Between different CT protocols of the same body region, radiation exposure varied up to 50% of the DRLs. CONCLUSION: The implemented cloud-based CT dose monitoring based on the DICOM-SR enables automated benchmarking in regard to national DRLs. Overall the local dose exposure from CT reached approximately 50% of these DRLs indicating that DRL actualization as well as protocol-specific DRLs are desirable. The cloud-based approach enables multi-center dose monitoring and offers great potential to further optimize radiation exposure in radiological departments. KEY POINTS: • The newly developed software based on the DICOM-Structured Report enables large-scale cloud-based CT dose monitoring • The implemented software solution enables automated benchmarking in regard to national DRLs • The local radiation exposure from CT reached approximately 50 % of the national DRLs • The cloud-based approach offers great potential for multi-center dose analysis.

Suspended photonic waveguide devices.

This article describes recent research at the U.S. Naval Research Laboratory that focuses on the use of micro- and nanomachining techniques for photonic waveguide devices. By selectively etching a sacrificial layer that the waveguide core is supported by, in whole or in part, the waveguide obtains enhanced properties and functionality, such as mechanical flexibility, index contrast, birefringence, and evanescent field depth. We describe how these properties enable unique waveguide applications in areas such as cavity optomechanics, displacement sensing, electro-optics, and nonlinear optics.

Dose monitoring using the DICOM structured report: assessment of the relationship between cumulative radiation exposure and BMI in abdominal CT.

AIM: To perform a systematic, large-scale analysis using the Digital Imaging and Communication in Medicine structured report (DICOM-SR) to assess the relationship between body mass index (BMI) and radiation exposure in abdominal CT. MATERIALS AND METHODS: A retrospective analysis of DICOM-SR of 3121 abdominal CT examinations between April 2013 and March 2014 was performed. All examinations were conducted using a 128 row CT system. Patients (mean age 61 ± 15 years) were divided into five groups according to their BMI: group A <20 kg/m(2) (underweight), group B 20-25 kg/m(2) (normal weight), group C 25-30 kg/m(2) (overweight), group D 30-35 kg/m(2) (obese), and group E > 35 kg/m(2) (extremely obese). CT dose index (CTDIvol) and dose-length product (DLP) were compared between all groups and matched to national diagnostic reference values. RESULTS: The mean CTDIvol and DLP were 5.4 ± 2.9 mGy and 243 ± 153 mGy.cm in group A, 6 ± 3.6 mGy and 264 ± 179 mGy.cm in group B, 7 ± 3.6 mGy and 320 ± 180 mGy.cm in group C, 8.1 ± 5.2 mGy and 375 ± 306 mGy.cm in group D, and 10 ± 8 mGy and 476 ± 403 mGy.cm in group E, respectively. Except for group A versus group B, CTDIvol and DLP differed significantly between all groups (p<0.05). Significantly more CTDIvol values exceeded national diagnostic reference values in groups D and E (2.1% and 6.3%) compared to group B (0.5%, p<0.05). CONCLUSION: DICOM-SR is a comprehensive, fast, and reproducible way to analyse dose-related data at CT. It allows for automated evaluation of radiation dose in a large study population. Dose exposition is related to the patient's BMI and is increased by up to 96% for extremely obese patients undergoing abdominal CT.

Evaluation of automated attenuation-based tube potential selection in combination with organ-specific dose reduction for contrast-enhanced chest CT examinations.

AIM: To evaluate the influence of attenuation-based tube potential selection (ATPS) in combination with organ-specific dose reduction (OSDR) on radiation dose and image quality of contrast-enhanced chest computed tomography (CT) examinations. MATERIAL AND METHODS: Seventy consecutive patients (59.2 ± 16.1 years; 49 men; 21 women) were randomized into two groups and underwent contrast-enhanced chest CT using a 128 section CT scanner. CT examinations were performed as standard protocol in group A (n = 35) and with the activated novel dose-saving devices, OSDR and ATPS, in group B (n = 35). Objective [signal-to-noise (SNR) and contrast-to-noise ratio (CNR)] and subjective image quality (five-point scale; 1 = non diagnostic; 5 = excellent) as well as radiation dose (CTDIvol) were analysed. RESULTS: CTDIvol of the protocol using OSDR and ATPS was significantly lower than in standard chest CT examinations (3.4 ± 1 versus 6.1 ± 2.3 mGy; p < 0.001). Although the level of noise was slightly elevated in group B (14.1 ± 1.7 versus 11.4 ± 1.9 HU; p < 0.01), no significant differences in SNR (17.1 ± 5 versus 16.3 ± 4.7) or subjective image quality (mean score of 4.6 versus 4.4) were observed between both imaging protocols. CONCLUSION: Attenuation-based tube potential selection in combination with organ-specific dose reduction essentially reduces the dose of chest CT in patients with normal body mass index (BMI) in clinical routine while maintaining subjective and objective image quality.

Feasibility of intensive multimodal therapy in infants affected by rhabdoid tumors - experience of the EU-RHAB registry.

Rhabdoid tumors mainly affect infants and other very young children with a marked vulnerability towards intensive therapy such as invasive surgery, high dose chemotherapy (HDCT) and dose intense radiotherapy. Radiotherapy (RT) is a promising option in rhabdoid tumors but its application in infants remains controversial. Neurocognitive and vascular side effects occur even long after completion of therapy. Therapeutic recommendations suggested by the European Rhabdoid Registry including RT, high dose chemotherapy (HDCT) and methotrexate (MTX) were developed by a consensus committee. Unique to our EU-RHAB database is the ability to analyze data of 64 of 81 registered infants (under one year of age) separate from older children. 20 (age at diagnoses 2-12 months) of these had received radiotherapy. To our knowledge, this is the first report specifically analyzing treatment data of infants suffering from malignant rhabdoid tumors. Our results suggest that radiotherapy significantly increases the mean survival time as well as the 3 year overall survival in infants. We detected a doubling of survival times in infants who received RT. Overall, our results suggest that infants benefit from RT with tolerable acute side effects. Severe long term sequelae likely due to intraventricular MTX and/or RT were reported in 4 patients (leukoencephalopathy). No differences in chemotherapy-related toxicity were observed between infants and children. We suggest that a nihilistic therapeutic approach towards young infants is not warranted and that RT may not be a priori rejected as a therapeutic option in infants.

Effects of an exercise intervention on bone mass in pediatric bone tumor patients.

The aim was to evaluate the effects of additional exercises during inpatient stays on bone mass in pediatric bone tumor patients. 21 patients were non-randomly allocated either to the exercise group (n = 10) or the control group (n = 11). DXA of the lumbar spine, the non-affected femur and both calcanei was performed after completion of neoadjuvant chemotherapy (baseline), as well as 6 and 12 months after baseline. Bone mineral content (BMC), bone mineral density (BMD) and height-corrected lumbar spine Z-scores were determined. Group changes after 6 and 12 months were compared by covariance analyses. Additionally, daily physical activities (PA) were assessed by means of accelerometry. After adjusting for initial age, height and weight, mean reductions in lumbar spine and femoral BMC were lower in the exercise group (not significant). Effect sizes during the observational period for lumbar spine and femur BMC were generally small (partial η² = 0.03). The exercise group demonstrated substantially higher PA levels in terms of gait cycles per day, per hour and moderate PA (activities above 40 gait cycles per minute). Additional exercises for bone tumor patients are feasible during hospitalization. Though the intervention did not influence BMC, it appeared beneficial regarding PA promotion with respect to volume and intensity.

MOON-test - determination of motor performance in the pediatric oncology.

BACKGROUND: Pediatric cancer patients suffer from various negative consequences due to the disease, the medical therapy and the inactivity during the intensive treatment. Only few studies have systematically identified the adverse effects of cancer on motor performance in childhood. METHODS: To determine the motor performance of pediatric cancer patients, a motor performance test was developed which is applicable for this specific patient group. Eight test items with reference values for healthy children were merged to the MOON-test (test for motor performance in the oncology). RESULTS: MOON was tested for feasibility and acceptance in 33 patients aged 4-18 years. Feasibility was confirmed for children with different types of cancer (hematological malignancies and solid tumors) and with amputation, endoprosthesis, during aplasia as well as reduced general condition. Furthermore the patients showed a broad acceptance. CONCLUSION: Based on the study findings, the use of MOON-test as a standardized motor performance diagnostic tool in clinical routine of oncological acute clinics as well as rehabilitation clinics can be recommended.·

Critical limb ischaemia: initial treatment and predictors of amputation-free survival.

OBJECTIVES: To evaluate initial treatment and risk factors for amputation-free survival in patients with critical limb ischaemia (CLI). DESIGN: Prospective clinical cohort study at a single vascular surgical centre in Germany. METHODS: Data on 104 consecutive patients (115 ischaemic limbs) presenting with their first episode of CLI were collected prospectively over a 3-year period. Initial treatment was classified as conservative therapy, intervention, surgery, or major amputation. Patient co-morbidities were assessed by uni- and multivariate analysis to determine risk factors for limb salvage, survival and amputation-free survival. RESULTS: Indications for treatment were rest pain in 27 (23.5%) and tissue loss in 88 (76.5%) limbs. Revascularisation was attempted in 65% of all limbs: 45% by intervention and 55% by surgery. In 9% primary amputation was necessary and 22% received conservative therapy. Median follow-up was 28 months (1-42). The 3-year limb salvage, patient survival, and amputation-free survival rates were 73%, 41%, and 31%, respectively. Diabetes, cardiac disease and renal insufficiency were associated with poor survival. Combined cardiac and renal disease adversely affected amputation-free survival (HR, 3.68; 95% CI, 1.51-8.94; P < 0.001). CONCLUSIONS: At least two third of all patients presenting with CLI can be offered some type of direct revascularisation. In patients with major cardiac disease and renal insufficiency, a poor outcome in terms of amputation-free survival is to be anticipated.

Demonstration of a mode-conversion cavity add-drop filter.

We experimentally demonstrate a new type of add-drop filter incorporating an asymmetric Y-branch waveguide coupler and a shifted-grating mode-conversion cavity. The device relies on mode separation in the asymmetric Y-branch and wavelength-selective mode conversion upon reflection from the shifted-grating cavity. Add-drop functionality is demonstrated in a three-port integrated silicon-on-insulator device.

Randomized clinical trials in children--ethical and methodological issues.

Randomization is an internationally accepted methodological tool used to perform sound clinical research. To ensure the clinical value of medical interventions, both evidence based medicine and new drug approvals require that randomized controlled trials (RCT) be conducted. Randomization prevents the manipulation of participant allocation and balances unknown confounders in a way no other method can. The gold standard RCT, however, is complex to conduct and requires significant financial and structural resources. In consequence, drug development and registration are primarily driven by the pharmaceutical industry. Within the field of pediatrics, we need high quality research tailored to children in order to reduce off-label use and to ensure that we expose children only to effective and, above all, safe drug treatments. The American and European regulatory authorities now offer programs to support such studies and clinical researchers and pharmaceutical industries are obliged to put them into practice in the best interest of the children. Issues relating to feasibility as well as ethical issues must be born in mind when planning RCTs in child populations. Obtaining informed assent from children in an adequate manner is one of several key elements. Moreover, it is essential to ensure equipoise before conducting a trial. Thus, issues relating to acceptability can be addressed and the discrimination of treatment groups within RCTs can be prevented. This narrative review addresses ethical and methodological aspects of RCTs in adults and especially in children and includes a quantitative analysis, which explores issues relating to the publication of RCTs.

Improved bleeding profile and tolerability of tibolone versus transdermal E2/NETA treatment in postmenopausal women with female sexual dysfunction.

OBJECTIVES: To compare the incidence of vaginal spotting/bleeding events and breast pain between therapy with tibolone 2.5 mg and continuous combined transdermal estradiol (E(2))/norethisterone acetate (NETA) 50 microg/140 microg after 24 weeks of treatment. METHODS: A double-blind, double-dummy, randomized, controlled trial was performed and assessments were performed at baseline, week 12 and week 24. Bleeding/spotting events were recorded in a daily diary. Breast signs and symptoms were collected as adverse events. RESULTS: A total of 403 women (mean age 56 years) were randomized. Bleeding/spotting events during weeks 1-12 with tibolone and E(2)/NETA were experienced by 16% and 56% of women, respectively (p < 0.001). The corresponding percentages during weeks 13-24 were 12% and 51%, respectively (p < 0.001). E(2)/NETA was significantly more likely than tibolone to be associated with vaginal hemorrhage (11% vs. 0%; p < 0.001) and breast signs and symptoms (11% vs. 4%; p = 0.015). Early discontinuations resulting from adverse events were significantly more common in the E(2)/NETA group than in the tibolone group (20% vs. 12%), primarily related to withdrawal due to vaginal hemorrhage (8% vs. 0%). CONCLUSIONS: Tibolone has a significantly better tolerability profile than transdermal E(2)/NETA as measured by vaginal bleeding, breast pain and treatment continuation.

Pharmacokinetic monitoring of intravenous cyclosporine A in pediatric stem-cell transplant recipients. The trough level is not enough.

In order to monitor CsA serum levels after SCT, trough levels (C0) are widely used. The aim of this study was to estimate the population and individual PK parameters for patients receiving intravenous CsA after SCT. In 27 pediatric patients after SCT receiving CsA (3 mg/kg/day) every 12 h, a total of 289 CsA concentrations was obtained. To describe the PK parameters of CsA, a two-compartment model with first order elimination was used. Covariate analysis identified body weight, age, and the co-administration with itraconazole and tobramycine as factors influencing the Cl. The statistical comparison of AUC, trough level, and C2 indicates a correlation between AUC and C2, but no correlation between the AUC and C0, r = 0.24 (p = 0.146) vs. r = 0.526 (p = 0.000692), respectively. Our results underscore the fact that CsA trough levels do not reflect the drug exposure in patients receiving intravenous CsA after SCT. By contrast, CsA blood levels measured 2-6 h after CsA infusion showed a better correlation with the AUC. Our data provide new information to optimize the balancing act between GvHD-prophylaxis, graft vs. leukemia effect, and CsA side-effects after SCT.