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BackgroundMultimorbidity increases healthcare resource utilization. Little is known on specific comorbidity combinations.AimsTo identify comorbidities associated with increased resource utilization among inpatients admitted for gastrointestinal bleeding (GIB).MethodsThis retrospective cross-sectional study, 1/2010–5/2018 at the University Hospital Zurich, Switzerland, analyzed electronic health records of patients with upper (UGIB) and lower (LGIB) GIB, focusing on length of stay (LOS) and 30-day readmissions for resource use and clinical outcomes, investigated by multivariable regression adjusted for antithrombotics.ResultsOf 1101 patients, 791 had UGIB and 310 LGIB, most often melena and bleeding diverticula, respectively. In UGIB, thromboembolic events showed a trend toward 27% increased LOS (1.27; 95% confidence interval [CI] 1.00–1.61), antithrombotics independently associated with 46% increased LOS (1.46; 95% CI 1.32–1.62). Cancer (odds ratio [OR] 2.86; 95% CI 1.68–4.88) independently associated with 30-day readmissions, anemia showed a trend (OR 1.68; 95% CI 1.00–2.84). In LGIB, none of the investigated comorbidities associated with increased LOS, but antithrombotics independently associated with 25% increased LOS (1.25; 95% CI 1.07–1.46). Atrial fibrillation/flutter (OR 2.69; 95% CI 1.06–6.82) and cancer (OR 4.76; 95% CI 1.40–16.20) associated strongly with 30-day readmissions.ConclusionsIn both groups, cancer associated with 30-day readmissions, antithrombotics with increased LOS. Thromboembolic events and anemia showed clinically important trends in UGIB. Atrial fibrillation/flutter associated with 30-day readmissions in LGIB. Prospective studies are needed to investigate these complex multimorbid populations and establish appropriate guidelines.

CCAAT/enhancer binding protein alpha ( CEBPA) mutations in AML are associated with favourable prognosis and are divided into N- and C-terminal mutations. The majority of AML patients have both types of mutations. We assessed the prognostic significance of single ( n =7) and double ( n =12) CEBPA mutations among 224 AML patients. Double CEBPA mutations conferred a decisively favourable overall ( P =0.006) and disease-free survival ( P =0.013). However, clinical outcome of patients with single CEBPA mutations was not different from CEBPA wild-type patients. In a multivariable analysis, only double – but not single – CEBPA mutations were identified as independent prognostic factors. These findings indicate heterogeneity within AML patients with CEBPA mutations.

The current paradigm on leukemogenesis indicates that leukemias are propagated by leukemic stem cells. The genomic events and pathways involved in the transformation of hematopoietic precursors into leukemic stem cells are increasingly understood. This concept is based on genomic mutations or functional dysregulation of transcription factors in malignant cells of patients with acute myeloid leukemia (AML). Loss of the CCAAT/enhancer binding protein-α ( CEBPA ) function in myeloid cells in vitro and in vivo leads to a differentiation block, similar to that observed in blasts from AML patients. CEBPA alterations in specific subgroups of AML comprise genomic mutations leading to dominant-negative mutant proteins, transcriptional suppression by leukemic fusion proteins, translational inhibition by activated RNA-binding proteins, and functional inhibition by phosphorylation or increased proteasomal-dependent degradation. The PU.1 gene can be mutated or its expression or function can be blocked by leukemogenic fusion proteins in AML. Point mutations in the RUNX1/AML1 gene are also observed in specific subtypes of AML, in addition to RUNX1 being the most frequent target for chromosomal translocation in AML. These data are persuasive evidence that impaired function of particular transcription factors contributes directly to the development of human AML, and restoring their function represents a promising target for novel therapeutic strategies in AML.

Background: High-dose chemotherapy with autologous stem cell transplantation is a cornerstone in the first-line treatment of multiple myeloma patients. However, only few factors have been identified affecting the outcome in such patients. We hypothesised that varying levels of mobilised CD34+ cells confer prognostic information in myeloma patients undergoing high-dose chemotherapy. Methods: We determined circulating CD34+ cells at the day of peripheral stem cell collection in 158 consecutive myeloma patients between January 2001 and August 2010. Patients were stratified into two groups (super vs normal mobilisers) with a cutoff of 100 000 peripheral CD34+ cells per ml. Results: We found that patients with more than 100 000 peripheral CD34+ cells per ml had a better overall survival ( P =0.005) and a prolonged time to progression ( P =0.0398) than patients with CD34+ cell counts below 100 000 CD34+ cells per ml. High levels of CD34+ cells were an independent marker for better overall survival and time to progression in a multivariate analysis that included disease stage, response at transplant, light-chain subtype, age, sex, and height. Conclusion: Our results suggest that high levels of mobilised peripheral CD34+ cells are associated with favourable outcome in myeloma patients undergoing autologous transplantation.

Background: CCAAT/enhancer-binding protein- α (CEBPA) is crucial for normal granulopoiesis and is frequently disrupted in acute myeloid leukaemia (AML). Increasing evidence suggests that CEBPA exerts its effects, in parts, by regulating specific microRNAs (miRNAs), as previously shown for miR-223 . The aim of this study was to investigate the genome-wide pattern of miRNAs regulated by CEBPA in myeloid cells. Methods: In Kasumi-1 cells, conditionally expressing CEBPA, we assessed the expression of 470 human miRNAs by microarray analysis. We further investigated the microarray results by qRT-PCR, luciferase reporter assays, and chromatin immunoprecipitation assays. Results: In all, 18 miRNAs were more than two-fold suppressed or induced after CEBPA restoration. Among these 18 miRNAs, we focused on CEBPA-mediated regulation of the tumour-suppressive miR-29b . We observed that miR-29b is suppressed in AML patients with impaired CEBPA function or loss of chromosome 7q. We found that CEBPA selectively regulates miR-29b expression on its miR-29a/b1 locus on chromosome 7q32.3, whereas miR-29b2/c on chromosome 1q32.2 is not affected. Conclusion: This study reports the activation of the tumour-suppressive miR-29b by the haematopoietic key transcription factor CEBPA. Our data provide a rationale for miR-29b suppression in AML patients with loss of chromosome 7q or CEBPA deficiency.

Early assessment of antiretroviral drug efficacy is important for prevention of the emergence of drug-resistant virus and unnecessary exposure to ineffective drug regimens. Current US guidelines for changing therapy are based on measurements of plasma HIV-1 RNA concentrations 4 or 8 weeks after the start of treatment with cut-off points of 0·75 or 1·00 log, respectively. We investigated the possibility of assessing drug efficacy from measurements of plasma HIV-1 concentrations made during the first week on therapy. The kinetics of virus decay in plasma during the first 12 weeks of treatment was analysed for 124 HIV-1-infected patients being treated for the first time with a protease inhibitor. Patients with a continuous decline of HIV-1 concentrations and in whom HIV-1 was either undetectable or declined by more than 1·5 log at 12 weeks were defined as good responders; the rest were poor responders. The individual virus decay rate constants (k) at day 6 correlated significantly ( r>0·66, p<0·0001) with changes in HIV-1 concentrations at 4, 8, and 12 weeks, and correctly predicted 84% of the responses with a cut-off value of k=0·21 per day (in log scale). Reduction in plasma HIV-1 of less than 0·72 log by day 6 after initiation of therapy predicted poor long-term responses in more than 99% of patients. These results suggest that changes in HIV-1 concentration at day 6 after treatment initiation are major correlates of longer-term virological responses. They offer a very early measure of individual long-term responses, suggesting that treatment could be optimised after only a few days of therapy.

Chemotherapy with G–CSF is used to mobilize peripheral stem cells in multiple myeloma (MM) patients, with plerixafor as a rescue strategy for poorly mobilizing patients. Preclinical studies suggested that the nonsteroidal anti-inflammatory drug meloxicam enhances the mobilization of CD34 + cells. In this single-center study, we evaluated whether adding meloxicam to chemotherapy/G–CSF mobilization increases peripheral hematopoietic CD34 + cell levels and reduces the need of using plerixafor. We prospectively compared two consecutive cohorts of MM patients in first remission mobilized with G–CSF and non-myelosuppressive chemotherapy with vinorelbine or gemcitabine. The second cohort additionally received oral meloxicam. The cohorts comprised 84 patients without meloxicam (−M) and 66 patients with meloxicam (+M). Meloxicam was well tolerated and associated with similar hematologic engraftment after transplantation and equal survival rates. However, the meloxicam group had higher CD34 + cell levels on day 8 of the mobilization procedure (53 200 versus 35 600 CD34 + cells/mL; P =0.007), and fewer patients needed >1 collection day (+M: 6 (9%) patients versus −M: 16 (19%) patients; P =0.04). This resulted in reduced plerixafor administrations (+M: 7 (11%) patients versus −M: 18 (21%) patients; P =0.03) and less costs. Our data suggest that meloxicam enhances the mobilization of hematopoietic CD34 + blood cells in MM patients.

The occurrence of varicella zoster virus (VZV) reactivation is increased after allogeneic transplantation, whereas limited data are available for herpes zoster (HZ) after autologous SCT (ASCT). We determined the incidence and the prognostic significance of HZ and its correlation with VZV serology in 191 consecutive myeloma patients undergoing high-dose melphalan chemotherapy with ASCT. We found that VZV reactivation occurred in 57 (30%) patients, in 8.5% during induction and in 21.5% after ASCT peaking at 8 months after ASCT. Disease burden due to HZ was assessed as high or rather high in 70% of the patients. By immune fluorescence and Serion Elisa VZV IgG assessment, 90.8% of all patients had specific anti-VZV antibodies at ASCT. Lower specific antibody titers at transplantation were observed in patients with HZ after ASCT than in those without reactivation ( P =0.009). Finally, OS was better in myeloma patients with HZ after ASCT compared with patients without HZ ( P =0.007). Our data indicate that VZV reactivation after ASCT is a frequent event carrying a significant disease burden and it is associated with improved survival. Low levels of specific VZV antibodies at ASCT suggest increased vulnerability for VZV reactivation.

The transcription factor C/EBPα (for CCAAT/enhancer binding protein-α; encoded by the gene CEBPA ) is crucial for the differentiation of granulocytes. Conditional expression of C/EBPα triggers neutrophilic differentiation, and no mature granulocytes are observed in Cebpa -mutant mice. Here we identify heterozygous mutations in CEBPA in ten patients with acute myeloid leukemia (AML). We found that five mutations in the amino terminus truncate the full-length protein, but did not affect a 30-kD protein initiated further downstream. The mutant proteins block wild-type C/EBPα DNA binding and transactivation of granulocyte target genes in a dominant-negative manner, and fails to induce granulocytic differentiation. Ours is the first report of CEBPA mutations in human neoplasia, and such mutations are likely to induce the differentiation block found in AML.

The majority of patients with acute myeloid leukemia (AML) still die of their disease, and novel therapeutic concepts are needed. Timely expression of the hematopoietic master regulator PU.1 is crucial for normal development of myeloid and lymphoid cells. Targeted disruption of an upstream regulatory element (URE) located several kb upstream in the PU.1 promoter decreases PU.1 expression thereby inducing AML in mice. In addition, suppression of PU.1 has been observed in specific subtypes of human AML. Here, we identified nuclear factor-κB ( NF-κB ) to activate PU.1 expression through a novel site within the URE. We found sequence variations of this particular NF-κB site in 4 of 120 AML patients. These variant NF-κB sequences failed to mediate activation of PU.1 . Moreover, the synergistic activation of PU.1 together with CEBPB through these variant sequences was also lost. Finally, AML patients with such variant sequences had suppressed PU.1 mRNA expression. This study suggests that changes of a single base pair in a distal element critically affect the regulation of the tumor suppressor gene PU.1 thereby contributing to the development of AML.