Showing papers by "Martin Granzow published in 2020"

Cytogenetic subclone formation and evolution in progressive smoldering multiple myeloma.

Abstract: Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Myeloma (SMM) consistently precede symptomatic Multiple Myeloma (MM) requiring systemic therapy [1]. Several factors have been identified to predict higher risk of progression in asymptomatic patients [2]. High-risk chromosomal aberrations (CA) are associated with an increased risk of progression into symptomatic myeloma [2–4]. The impact of subclones and clonal evolution during progression of asymptomatic myeloma has not been extensively studied. So far only two published studies analyzed paired samples acquired at the time-point of MGUS/SMM and after progression into MM [5, 6]. In the current study, we investigated the presence of subclonal CA in patients with SMM and correlated findings with established baseline risk factors for disease progression as well as outcome. Second, we analyzed paired samples from SMM patients with and without progression into MM to characterize clonal evolution. We identified 191 eligible SMM patients for our analyses. Longitudinal samples were available in 67 SMM patients, in 43 patients after progression into MM and in 24 patients still at the stage of SMM without progression. We also included 139 patients with iFISH analyses at primary diagnosis and relapse after autologous stem cell transplantation (ASCT) who were previously reported [7] to illustrate the impact of selection pressure imposed by systemic therapy. Analyses were approved by the local ethics committee and performed in accordance with the Declaration of Helsinki. iFISH was performed using the following probes: 1q21, 5p15, 5q35, 8p21, 9q34, 11q23, 13q14, 15q22, 17p13, and 19q13, the translocation probes t(4;14), t(11;14), and t (14;16) as well as a probe for IgH rearrangements. Threshold for all aberrations was 10%. As described previously [8, 9], subclones were defined by a clone size smaller than two thirds of the largest clone and an absolute difference of at least 30%. Hyperdiploidy (HD) was defined by gains of at least two odd-numbered chromosomes, the presence of gain 1q21, del 17p13, t(4;14) and t(14;16) defined high-risk CA. Detailed statistical analyses can be found in the supplemental material. Of the 191 patients, 114 harbored subclones. Analyses of baseline characteristics revealed no significant differences between SMM patients with or without subclones at primary diagnosis (Supplementary Table 1). Follow-up data were available in 171 SMM patients. During a median follow-up of 61 months, 76 events occurred. Rate of progression was 29.5% at two years for the entire cohort. Patients with an elevated M-Protein and BMPC had a twoyear progression rate of 65.1% (Fig. 1a). We confirmed that the presence of t(4;14), del 17p13, gain 1q21, del 8p21, and del 13q14 were linked to higher risk of progression. The effects were more pronounced if the respective CA were present as main clone instead of subclone. Figure 1d summarizes results of univariate analyses. The presence of any subclone was not prognostic in the overall cohort (HR 0.91 [0.58;1.44], p= 0.7), but the * Maximilian Merz maximilian.merz@med.uni-heidelberg.de

Comparative expression profiling in the intestine of patients with Giardia-induced postinfectious functional gastrointestinal disorders.

Abstract: Background A Giardia outbreak in Bergen, Norway, caused postinfectious functional gastrointestinal disorders (PI-FGIDs). Despite the devastating effects of this outbreak, it presented a unique chance to investigate the implication on the dysregulation of genetic pathways in PI-FGID. Methods We performed the first comparative expression profiling of miRNAs and their potential target genes in microdissected rectal biopsies from 20 Giardia-induced PI-FGID patients vs 18 healthy controls by nCounter analysis. Subsequently, candidates were validated on protein level by immunostaining. Key results miRNA profiling on rectal biopsy samples from 5 diarrhea-predominant PI-IBS cases compared to 10 healthy controls revealed differential expression in the epithelial layer. The top five regulated miRNAs were implicated in GI disease, inflammatory response, and immunological disease. Subsequently, these miRNAs and 100 potential mRNA targets were examined in 20 PI-FGID cases and 18 healthy controls in both the mucosal epithelium and the lamina propria. Although deregulation of the selected miRNAs could not be verified in the larger sample set, mRNAs involved in barrier function were downregulated in the epithelium. Pro-inflammatory genes and genes implicated in epigenetic modifications were upregulated in the lamina propria. Immunostaining for selected candidates on 17 PI-FGID cases and 16 healthy controls revealed increased tryptase levels as well as a decreased and aberrant subcellular expression of occludin. Conclusions and inferences Genes relevant to immune and barrier function as well as stress response and epigenetic modulation are differentially expressed in PI-FGIDs and may contribute to disease manifestation.