Dendritic cell reconstitution is associated with relapse-free survival and acute GVHD severity in children after allogeneic stem cell transplantation

DCs are potent APCs and key regulators of innate and adaptive immunity. After allo-SCT, their reconstitution in the peripheral blood (PB) to levels similar to those in healthy individuals tends to be slow. We investigate the age- and sex-dependant immune reconstitution of myeloid (mDC) and plasmacytoid DC (pDC) in the PB of 45 children with leukaemia or myelodysplastic syndrome (aged 1-17 years, median 10) after allo-SCT with regard to relapse, acute GVHD (aGVHD) and relapse-free survival. Low pDC/μL PB up to day 60 post SCT are associated with higher incidence of moderate or severe aGVHD (P=0.035), whereas high pDC/μL PB up to day 60 are associated with higher risk of relapse (P<0.001). The time-trend of DCs/μL PB for days 0-200 is a significant predictor of relapse-free survival for both mDCs (P<0.001) and pDCs (P=0.020). Jointly modelling DC reconstitution and complications improves on these simple criteria. Compared with BM, PBSC transplants tend to show slower mDC/pDC reconstitution (P=0.001, 0.031, respectively), but have no direct effect on relapse-free survival. These results suggest an important role for both mDCs and pDCs in the reconstituting immune system. The inclusion of mDCs and pDCs may improve existing models for complication prediction following allo-SCT

Liposomal amphotericin B twice weekly as antifungal prophylaxis in paediatric haematological malignancy patients

AbstractData on antifungal prophylaxis in paediatric cancer patients at high risk for invasive fungal disease (IFD) are scant. Intermittent administration of liposomal amphotericin B (LAMB) has been shown to be safe and effective in adult patients with haematological malignancies. We prospectively evaluated the safety and efficacy of prophylactic LAMB at a dosage of 2.5 mg/kg twice weekly in children at high risk for IFD. Efficacy was compared with that in a historical control group of patients with similar demographic characteristics not receiving LAMB prophylaxis. A total of 46 high-risk patients (24 boys; mean age, 7.7 years) with 187 episodes of antifungal prophylaxis were analysed. The median duration of neutropenia (<500/µL) was 10 days. LAMB was discontinued in four patients because of acute allergic reactions. Median values for creatinine and liver enzymes at end of treatment did not differ significantly from those at baseline. Hypokalaemia (<3.0 mmol/L) occurred with 13.5% of the prophylactic episodes, but was usually mild and always reversible. No proven/probable IFD occurred in patients receiving LAMB prophylaxis. In comparison, five proven and two probable IFDs were observed in 45 historical controls not receiving LAMB prophylaxis (p 0.01). LAMB prophylaxis had no impact on the use of empirical antifungal therapy. Systemic antifungal prophylaxis with LAMB 2.5 mg/kg twice weekly is feasible and safe, and seems to be an effective approach for antifungal prophylaxis in high-risk paediatric cancer patients

Proteomic analysis of the cerebrospinal fluid of patients with Creutzfeldt-Jakob disease

So far, only the detection of 14-3-3 proteins in cerebrospinal fluid (CSF) has been accepted as diagnostic criterion for Creutzfeldt-Jakob disease (CJD). However, this assay cannot be used for screening because of the high rate of false-positive results, whereas patients with variant CJD are often negative for 14-3-3 proteins. The aim of this study was to compare the spot patterns of CSF by 2-dimensional polyacrylamide gel electrophoresis (2D-PAGE) to search for a CJD-specific spot pattern. We analyzed the CSF of 28 patients {[}11 CJD, 9 Alzheimer's disease ( AD), 8 nondemented controls (NDC)] employing 2D-PAGE which was optimized for minimal volumes of CSF (0.1 ml; 7-cm strips). All samples were run at least three times, gels were silver stained and analyzed by an analysis software and manually revised. We could consistently match 268 spots which were then compared between all groups. By the use of 5 spots, we were able to differentiate CJD from AD or NDC with a sensitivity of 100%. CJD could also be distinguished from both groups by using a heuristic clustering algorithm of 2 spots. We conclude that this proteomic approach can differentiate CJD from other diseases and may serve as a model for other neurodegenerative diseases. Copyright (C) 2007 S. Karger AG, Basel

Value of T2 Mapping MRI for Prostate Cancer Detection and Classification.

Currently, multi-parametric prostate MRI (mpMRI) consists of a qualitative T &lt;sub&gt;2&lt;/sub&gt; , diffusion weighted, and dynamic contrast enhanced imaging. Quantification of T &lt;sub&gt;2&lt;/sub&gt; imaging might further standardize PCa detection and support artificial intelligence solutions. To evaluate the value of T &lt;sub&gt;2&lt;/sub&gt; mapping to detect prostate cancer (PCa) and to differentiate PCa aggressiveness. Retrospective single center cohort study. Forty-four consecutive patients (mean age 67 years; median PSA 7.9 ng/mL) with mpMRI and verified PCa by subsequent targeted plus systematic MR/ultrasound (US)-fusion biopsy from February 2019 to December 2019. Standardized mpMRI at 3 T with an additionally acquired T &lt;sub&gt;2&lt;/sub&gt; mapping sequence. Primary endpoint was the analysis of quantitative T &lt;sub&gt;2&lt;/sub&gt; values and contrast differences/ratios (CD/CR) between PCa and benign tissue. Secondary objectives were the correlation between T &lt;sub&gt;2&lt;/sub&gt; values, ISUP grade, apparent diffusion coefficient (ADC) value, and PI-RADS, and the evaluation of thresholds for differentiating PCa and clinically significant PCa (csPCa). Mann-Whitney test, Spearman's rank (r &lt;sub&gt;s&lt;/sub&gt; ) correlation, receiver operating curves, Youden's index (J), and AUC were performed. Statistical significance was defined as P &lt; 0.05. Median quantitative T &lt;sub&gt;2&lt;/sub&gt; values were significantly lower for PCa in PZ (85 msec) and PCa in TZ (75 msec) compared to benign PZ (141 msec) or TZ (97 msec) (P &lt; 0.001). CD/CR between PCa and benign PZ (51.2/1.77), respectively TZ (19.8/1.29), differed significantly (P &lt; 0.001). The best T &lt;sub&gt;2&lt;/sub&gt; -mapping threshold for PCa/csPCa detection was for TZ 81/86 msec (J = 0.929/1.0), and for PZ 110 msec (J = 0.834/0.905). Quantitative T &lt;sub&gt;2&lt;/sub&gt; values of PCa did not correlate significantly with the ISUP grade (r &lt;sub&gt;s&lt;/sub&gt; = 0.186; P = 0.226), ADC value (r &lt;sub&gt;s&lt;/sub&gt; = 0.138; P = 0.372), or PI-RADS (r &lt;sub&gt;s&lt;/sub&gt; = 0.132; P = 0.392). Quantitative T &lt;sub&gt;2&lt;/sub&gt; values could differentiate PCa in TZ and PZ and might support standardization of mpMRI of the prostate. Different thresholds seem to apply for PZ and TZ lesions. However, in the present study quantitative T &lt;sub&gt;2&lt;/sub&gt; values were not able to indicate PCa aggressiveness. 2 TECHNICAL EFFICACY: Stage 2

Long term outcome of high-risk neuroblastoma patients after immunotherapy with antibody ch14.18 or oral metronomic chemotherapy

Background: The treatment of high-risk neuroblastoma patients consists of multimodal induction therapy to achieve remission followed by consolidation therapy to prevent relapses. However, the type of consolidation therapy is still discussed controversial. We applied metronomic chemotherapy in the prospective NB90 trial and monoclonal anti-GD2-antibody (MAB) ch14.18 in the NB97 trial. Here, we present the long term outcome data of the patient cohort. Methods: A total of 334 stage 4 neuroblastoma patients one year or older were included. All patients successfully completed the induction therapy. In the NB90 trial, 99 patients received at least one cycle of the oral maintenance chemotherapy (NB90 MT, 12 alternating cycles of oral melphalan/etoposide and vincristine/cyclophosphamide). In the NB97 trial, 166 patients commenced the MAB ch14.18 consolidation therapy (six cycles over 12 months). Patients who received no maintenance therapy according to the NB90 protocol or by refusal in NB97 (n = 69) served as controls. Results: The median observation time was 11.11 years. The nine-year event-free survival rates were 41 ± 4%, 31 ± 5%, and 32 ± 6% for MAB ch14.18, NB90 MT, and no consolidation, respectively (p = 0.098). In contrast to earlier reports, MAB ch14.18 treatment improved the long-term outcome compared to no additional therapy (p = 0.038). The overall survival was better in the MAB ch14.18-treated group (9-y-OS 46 ± 4%) compared to NB90 MT (34 ± 5%, p = 0.026) and to no consolidation (35 ± 6%, p = 0.019). Multivariable Cox regression analysis revealed ch14.18 consolidation to improve outcome compared to no consolidation, however, no difference between NB90 MT and MAB ch14.18-treated patients was found. Conclusions: Follow-up analysis of the patient cohort indicated that immunotherapy with MAB ch14.18 may prevent late relapses. Finally, metronomic oral maintenance chemotherapy also appeared effective

Thermodynamic correction of particle concentrations measured by underwing probes on fast flying aircraft

Particle concentration measurements with underwing probes on aircraft are impacted by air compression upstream of the instrument body as a function of flight velocity. In particular for fast-flying aircraft the necessity arises to account for compression of the air sample volume. Hence, a correction procedure is needed to invert measured particle number concentrations to ambient conditions that is commonly applicable for different instruments to gain comparable results. In the compression region where the detection of particles occurs (i.e. under factual measurement conditions), pressure and temperature of the air sample are increased compared to ambient (undisturbed) conditions in certain distance away from the aircraft. Conventional procedures for scaling the measured number densities to ambient conditions presume that the particle penetration speed through the instruments' detection area equals the aircraft speed (True Air Speed, TAS). However, particle imaging instruments equipped with pitot-tubes measuring the Probe Air Speed (PAS) of each underwing probe reveal PAS values systematically below those of the TAS. We conclude that the deviation between PAS and TAS is mainly caused by the compression of the probed air sample. From measurements during two missions in 2014 with the German Gulfstream G-550 (HALO – High Altitude LOng range) research aircraft we develop a procedure to correct the measured particle concentration to ambient conditions using a thermodynamic approach. With the provided equation the corresponding concentration correction factor ξ is applicable to the high frequency measurements of each underwing probe which is equipped with its own air speed sensor (e.g. a pitot-tube). ξ-values of 1 to 0.85 are calculated for air speeds (i.e. TAS) between 60 and 260 m s−1. From HALO data it is found that ξ does not significantly vary between the different deployed instruments. Thus, for the current HALO underwing probe configuration a parameterisation of ξ as a function of TAS is provided for instances if PAS measurements are lacking. The ξ-correction yields higher ambient particle concentration by about 15–25 % compared to conventional procedures – an improvement which can be considered as significant for many research applications. The calculated ξ-values are specifically related to the considered HALO underwing probe arrangement and may differ for other aircraft or instrument geometries. Moreover, the ξ-correction may not cover all impacts originating from high flight velocities and from interferences between the instruments and, e.g., the aircraft wings and/or fuselage. Consequently, it is important that PAS (as a function of TAS) is individually measured by each probe deployed underneath the wings of a fast-flying aircraft

A tandem approach for collocated measurements of microphysical and radiative cirrus properties

Microphysical and radiation measurements were collected with the novel AIRcraft TOwed Sensor Shuttle (AIRTOSS) – Learjet tandem platform. The platform is a combination of an instrumented Learjet 35A research aircraft and an aerodynamic bird, which is detached from and retracted back to the aircraft during flight via a steel wire with a length of 4000 m. Both platforms are equipped with radiative, cloud microphysical, trace gas, and meteorological instruments. The purpose of the development of this tandem set-up is to study the inhomogeneity of cirrus as well as other stratiform clouds. Sophisticated numerical flow simulations were conducted in order to optimally integrate an axially asymmetric Cloud Combination Probe (CCP) inside AIRTOSS. The tandem platform was applied during measurements at altitudes up to 36 000 ft (10 970 m) in the framework of the AIRTOSS – Inhomogeneous Cirrus Experiment (AIRTOSS-ICE). Ten flights were performed above the North Sea and Baltic Sea to probe frontal and in situ formed cirrus, as well as anvil outflow cirrus. For one flight, cirrus microphysical and radiative properties displayed significant inhomogeneities resolved by both measurement platforms. The CCP data show that the maximum of the observed particle number size distributions shifts with decreasing altitude from 30 to 300 µm, which is typical for frontal, midlatitude cirrus. Theoretical considerations imply that cloud particle aggregation inside the studied cirrus is very unlikely. Consequently, diffusional growth was identified to be the dominant microphysical growth process. Measurements of solar downward and upward irradiances at 670 nm wavelength were conducted above, below, and in the cirrus on both the Learjet and AIRTOSS. The observed variability of the downward irradiance below the cirrus reflects the horizontal heterogeneity of the observed thin cirrus. Vertically resolved solar heating rates were derived by either using single-platform measurements at different altitudes or by making use of the collocated irradiance measurements at different altitudes of the tandem platform. Due to unavoidable biases of the measurements between the individual flight legs, the single-platform approach failed to provide a realistic solar heating rate profile, while the uncertainties of the tandem approach are reduced. Here, the solar heating rates range up to 6 K day−1 at top of the cirrus layer

A Development Environment for Visual Physics Analysis

The Visual Physics Analysis (VISPA) project integrates different aspects of physics analyses into a graphical development environment. It addresses the typical development cycle of (re-)designing, executing and verifying an analysis. The project provides an extendable plug-in mechanism and includes plug-ins for designing the analysis flow, for running the analysis on batch systems, and for browsing the data content. The corresponding plug-ins are based on an object-oriented toolkit for modular data analysis. We introduce the main concepts of the project, describe the technical realization and demonstrate the functionality in example applications