Christel Weiss

Phase 2 study of oral panobinostat (LBH589) with or without erythropoietin in heavily transfusion-dependent IPSS low or int-1 MDS patients

Phase 2 study of oral panobinostat (LBH589) with or without erythropoietin in heavily transfusion-dependent IPSS low or int-1 MDS patients

Influence of body mass index on induction of labor: A historical cohort study

We aimed to determine the influence of body mass index (BMI) on induction of labor.

Genomic CDKN2A/2B deletions in adult Ph+ ALL are adverse despite allogeneic stem cell transplantation

We investigated the role of copy number alterations to refine risk stratification in adult Philadelphia chromosome positive (Ph)+ acute lymphoblastic leukemia (ALL) treated with tyrosine kinase inhibitors (TKIs) and allogeneic stem cell transplantation (aSCT). Ninety-seven Ph+ ALL patients (median age 41 years; range 18-64 years) within the prospective multicenter German Multicenter ALL Study Group studies 06/99 (n = 8) and 07/2003 (n = 89) were analyzed. All patients received TKI and aSCT in first complete remission (CR1). Copy number analysis was performed with single nucleotide polymorphism arrays and validated by multiplex ligation-dependent probe amplification. The frequencies of recurrently deleted genes were: IKZF1, 76%; CDKN2A/2B, 45%; PAX5, 43%; BTG1, 18%; EBF1, 13%; ETV6, 5%; RB, 14%. In univariate analyses, the presence of CDKN2A/2B deletions had a negative impact on all endpoints: overall survival (P = .023), disease-free survival (P = .012), and remission duration (P = .036). The negative predictive value of CDKN2A/2B deletions was retained in multivariable analysis along with other factors such as timing of TKI therapy, intensity of conditioning, achieving remission after induction phase 1 and BTG1 deletions. We therefore conclude that acquired genomic CDKN2A/2B deletions identify a subgroup of Ph+ ALL patients, who have an inferior prognosis despite aSCT in CR1. Their poor outcome was attributable primarily to a high relapse rate after aSCT.

Monitoring and predicting disease activity in autoimmune pancreatitis with the M-ANNHEIM-AiP-Activity-Score

BACKGROUND & OBJECTIVESnAutoimmune pancreatitis (AiP) is treated by immunosuppressive therapy. Exact description of disease activity of AiP is essential in clinical practice and research, but a score to describe the disease activity is missing. Thus, we aimed to establish an activity score of AiP.nnnMETHODSnWe retrospectively studied long-term disease courses of 29 patients with AiP (Mannheim, Germany), receiving corticosteroid treatment (CST) by analyzing 613 treatment appointments. Two assumptions were made: First, disease activity is higher at emergency treatments; second, disease activity drops under CST. In all patients, we evaluated established activity- and classification-systems of chronic pancreatitis (cP). Based on the most suitable system, we established an activity score of AiP by including AiP-specific parameters identified from our long-term disease courses and the literature. The new AiP-specific activity score was validated in an external cohort of 14 patients with AiP (Stockholm, Sweden).nnnRESULTSnWithin published activity indexes of cP, the M-ANNHEIM-classification most significantly correlated with emergency- and treatment-dependent disease activities (pxa0<xa00.001 and pxa0<xa00.01, conditional-logistic-regression-analysis). Significant correlations of disease activity were found for several clinical parameters (biliary involvement, extrapancreatic lesions, acute pancreatitis, focal pancreatic mass, pancreatic sausage/mass, focal enlargement, ascites; pxa0<xa00.05, Wilcoxon-signed-rank-test). Based on these data and disease features from the literature, the M-ANNHEIM-AiP-Activity-Score (MAAS) was established. CST-induced reduction of MAAS disease activity of more than 60% was associated with lower relapse rates (pxa0<xa00.05; Chi-Square-test). The results were validated in the external patient cohort.nnnCONCLUSIONnThe MAAS might represent a useful tool to monitor AiP.

Correction to: The EURO-FORTA (Fit fOR The Aged) List: International Consensus Validation of a Clinical Tool for Improved Drug Treatment in Older People

BackgroundDrug treatment of older people is still potentially inappropriate in many cases as multimorbidity and related polypharmacy are highly prevalent. To increase the quality of drug treatment in older people, the FORTA (Fit fOR The Aged) List (first version 2012) was developed in a Delphi consensus procedure and updated (FORTA2015) by 21 experts from Germany and Austria. It has been validated in a randomized, controlled, prospective trial demonstrating significant improvement in the quality of drug treatment and clinical endpoints (VALFORTA).MethodsBased on these results, Delphi consensus validations (two rounds) of country/region-specific FORTA Lists were conducted in the UK/Ireland, France, Poland, Italy, Spain, the Nordic countries and The Netherlands. An algorithm based on geriatric/pharmacologic expertise, publications and professional position was used to find experts in the field.ResultsForty-seven experts agreed to participate in the Delphi process (return rate of 97.9%). For each country/region, the overall mean consensus coefficient (deviation from the initiator proposal) wasxa0>xa00.9. FORTA Lists from six countries/regions with a minimum of four participating experts (excluding The Netherlands) plus the original FORTA List were collated into the EURO-FORTA List containing 264 items in 26 main indication groups. Two drugs had to be added to the proposed items, as proposed by at least four countries/regions; none had to be removed.ConclusionThis project produced seven new country/region-specific FORTA Lists, as well as the overarching EURO-FORTA List showing a high consensual level based on a broader expert base. EURO-FORTA should help to spread the FORTA approach and improve geriatric pharmacotherapy internationally.

Detecting Anti-IIa and Anti-Xa Direct Oral Anticoagulant (DOAC) Agents in Urine using a DOAC Dipstick

&NA; The assessment of the anticoagulant effect of direct oral anticoagulants (DOACs) can be important for rapid medical decision‐making, especially in patients needing immediate management. An assay that screens for the absence or presence of a DOAC would help accelerate treatment in these situations. Chromogenic and coagulation methods have several limitations, including limited accuracy, long turnaround time, and their need of specialized laboratories. Oral factor Xa and thrombin inhibitors are also eliminated by the kidneys and can be detected in patient urine samples using a single, rapid, sensitive, and patient‐specific qualitative assay. In these tests, the presence or absence of a DOAC in urine can be identified by visually observing specific colors after a few minutes. Several studies have demonstrated the robustness and repeatability of these assays. The specific colors of the test strip also detect creatinine in the urine, which shows whether DOAC excretion is reduced, thus suggesting renal impairment. Persons with amblyopia may use a specific reader. Current indications for using the DOAC Dipstick test include emergency medical situations with severe bleeding and thrombotic events or before urgent major surgical interventions to accelerate medical decision‐making.

Intra-breath-hold residual motion of image-guided DIBH liver-SBRT: An estimation by ultrasound-based monitoring correlated with diaphragm position in CBCT

BACKGROUND AND PURPOSEnCraniocaudal motion during image-guided abdominal SBRT can be reduced by computer-controlled deep-inspiratory-breath-hold (DIBH). However, a residual motion can occur in the DIBH-phases which can only be detected with intrafractional real-time-monitoring. We assessed the intra-breath-hold residual motion of DIBH and compared residual motion of target structures during DIBH detected by ultrasound (US). US data were compared with residual motion of the diaphragm-dome (DD) detected in the DIBH-CBCT-projections.nnnPATIENTS AND METHODSnUS-based monitoring was performed with an experimental US-system simultaneously to DIBH-CBCT acquisition. A total of 706 DIBHs during SBRT-treatments of metastatic lesions (liver, spleen, adrenal) of various primaries were registered in 13 patients. Residual motion of the target structure was documented with US during each DIBH. Motion of the DD was determined by comparison to a reference phantom-scan taking the individual geometrical setting at a given projection angle into account. Residual motion data detected by US were correlated to those of the DD (DIBH-CBCT-projection).nnnRESULTSnUS-based monitoring could be performed in all cases and was well tolerated by all patients. Additional time for daily US-based setup required 8u202f±u202f4u202fmin. 385 DIBHs of 706 could be analyzed. In 59% of all DIBHs, residual motion was below 2u202fmm. In 36%, residual motion of 2-5u202fmm and in 4% of 5-8u202fmm was observed. Only 1% of all DIBHs and 0.16% of all readings revealed a residual motion of >8u202fmm during DIBH. For DIBHs with a residual motion over 2u202fmm, 137 of 156 CBCT-to-US curves had a parallel residual motion and showed a statistical correlation.nnnDISCUSSION AND CONCLUSIONnSoft-tissue monitoring with ultrasound is a fast real-time method without additional radiation exposure. Computer-controlled DIBH has a residual motion of <5u202fmm in >95% which is in line with the published intra-breath-hold-precision. Larger intrafractional deviations can be avoided if the beam is stopped at an US-defined threshold.

Donor dopamine does not affect liver graft survival: Evidence of safety from a randomized controlled trial

Treatment of donation after brain death (DBD) donors with low‐dose dopamine improves the outcomes after kidney and heart transplantation. This study investigates the course of liver allografts from multiorgan donors enrolled in the randomized dopamine trial between 2004 and 2007 (clinicaltrials.gov identifier: NCT00115115). There were 264 hemodynamically stable DBDs who were randomly assigned to receive low‐dose dopamine. Dopamine was infused at 4 μg/kg/minute for a median duration of 6.0 hours (interquartile range, 4.4‐7.5 hours). We assessed the outcomes of 212 liver transplantations (LTs) performed at 32 European centers. Donors and recipients of both groups were very similar in baseline characteristics. Pretransplant laboratory Model for End‐Stage Liver Disease score was not different in recipients of a dopamine‐treated versus untreated graft (18 ± 8 versus 20 ± 8; P = 0.12). Mean cold ischemia time was 10.6 ± 2.9 versus 10.1 ± 2.8 hours (P = 0.24). No differences occurred in biopsy‐proven rejection episodes (14.4% versus 15.7%; P = 0.85), requirement of hemofiltration (27.9% versus 31.5%; P = 0.65), the need for early retransplantation (5.8% versus 6.5%; P > 0.99), the incidence of primary nonfunction (7.7% versus 8.3%; P > 0.99), and in‐hospital mortality (15.4% versus 14.8%; P > 0.99). Graft survival was 71.2% versus 73.2% and 59.6% versus 62.0% at 2 and 3 years (log‐rank P = 0.71). Patient survival was 76.0% versus 78.7% and 65.4% versus 69.4% at 1 and 3 years (log‐rank P = 0.50). In conclusion, donor pretreatment with dopamine has no short‐term or longterm effects on outcome after LT. Therefore, low‐dose dopamine pretreatment can safely be implemented as the standard of care in hemodynamically stable DBDs.

Strain-dependent effects of clinical echovirus 30 outbreak isolates at the blood-CSF barrier

BackgroundEchovirus (E) 30 (E-30) meningitis is characterized by neuroinflammation involving immune cell pleocytosis at the protective barriers of the central nervous system (CNS). In this context, infection of the blood-cerebrospinal fluid barrier (BCSFB), which has been demonstrated to be involved in enteroviral CNS pathogenesis, may affect the tight junction (TJ) and adherens junction (AJ) function and morphology.MethodsWe used an in vitro human choroid plexus epithelial (HIBCPP) cell model to investigate the effect of three clinical outbreak strains (13-311, 13-759, and 14-397) isolated in Germany in 2013, and compared them to E-30 Bastianni. Conducting transepithelial electrical resistance (TEER), paracellular dextran flux measurement, quantitative real-time polymerase chain reaction (qPCR), western blot, and immunofluorescence analysis, we investigated TJ and AJ function and morphology as well as strain-specific E-30 infection patterns. Additionally, transmission electron and focused ion beam microscopy electron microscopy (FIB-SEM) was used to evaluate the mode of leukocyte transmigration. Genome sequencing and phylogenetic analyses were performed to discriminate potential genetic differences among the outbreak strains.ResultsWe observed a significant strain-dependent decrease in TEER with strains E-30 Bastianni and 13-311, whereas paracellular dextran flux was only affected by E-30 Bastianni. Despite strong similarities among the outbreak strains in replication characteristics and particle distribution, strain 13-311 was the only outbreak isolate revealing comparable disruptive effects on TJ (Zonula Occludens (ZO) 1 and occludin) and AJ (E-cadherin) morphology to E-30 Bastianni. Notwithstanding significant junctional alterations upon E-30 infection, we observed both para- and transcellular leukocyte migration across HIBCPP cells. Complete genome sequencing revealed differences between the strains analyzed, but no explicit correlation with the observed strain-dependent effects on HIBCPP cells was possible.ConclusionThe findings revealed distinct E-30 strain-specific effects on barrier integrity and junctional morphology. Despite E-30-induced barrier alterations leukocyte trafficking did not exclusively occur via the paracellular route.

Capsule and fimbriae modulate the invasion of Haemophilus influenzae in a human blood-cerebrospinal fluid barrier model

The Gram-negative bacterium Haemophilus influenzae (H. influenzae) can commensally colonize the upper respiratory tract, but also cause life threatening disease including epiglottitis, sepsis and meningitis. The H. influenzae capsule protects the bacteria against both phagocytosis and opsonization. Encapsulated H. influenzae strains are classified into serotypes ranging from a to f dependent on their distinct polysaccharide capsule. Due to the implementation of vaccination the incidence of invasive H. influenzae type b (Hib) infections has strongly decreased and infections with other capsulated types, including H. influenzae type f (Hif), are emerging. The pathogenesis of H. influenzae meningitis is not clarified. To enter the central nervous system (CNS) the bacteria generally have to cross either the blood-brain barrier (BBB) or the blood-cerebrospinal fluid barrier (BSCFB). Using a cell culture model of the BCSFB based on human choroid plexus papilloma (HIBCPP) cells and different H. influenzae strains we investigated whether Hib and Hif invade the cells, and if invasion differs between encapsulated vs. capsular-deficient and fimbriated vs. non-fimbriated variants. We find that Hib can adhere to and invade into HIBCPP cells. Invasion occurs in a strongly polar fashion, since the bacteria enter the cells preferentially from the basolateral blood side. Fimbriae and capsule attenuate invasion into choroid plexus (CP) epithelial cells, and capsulation can influence the bacterial distribution pattern. Finally, analysis of clinical Hib and Hif isolates confirms the detected invasive properties of H. influenzae. Our data point to roles of capsule and fimbriae during invasion of CP epithelial cells.