A subset of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) show complex karyotype (CK), and these cases include a relatively high proportion of cases of therapy-related myeloid neoplasms and TP53 mutations. We aimed to evaluate the clinicopathologic features of outcome of 299 AML and MDS patients with CK. Mutations were present in 287 patients (96%) and the most common mutation detected was in TP53 gene (83%). A higher frequency of TP53 mutations was present in therapy-related cases (p=0.008) with a trend for worse overall survival (OS) in therapy-related patients as compared with de novo (p=0.08) and within the therapy-related group, the presence of TP53 mutation strongly predicted for worse outcome (p=0.0017). However, there was no difference in survival between CK patients based on categorization of AML versus MDS, (p=0.96) or presence of absence of circulating blasts ≥1% (p=0.52). TP53 mutated patients presented with older age (p=0.06) and lower hemoglobin (p=0.004) and marrow blast (p=0.02) compared to those with CK lacking TP53 mutation. Multivariable analysis identified presence of multi-hit TP53 mutation as strongest predictor of worse outcome, while neither a diagnosis of AML versus MDS nor therapy-relatedness independently influenced OS. Our findings suggest that among patients with MDS and AML, the presence of TP53 mutation (in particular multi-hit TP53 mutation) in the context of CK identifies a homogeneously aggressive disease, irrespective of the blast count at presentation or therapy-relatedness. The current classification of these cases into different disease categories artificially separates a single biologic disease entity.
In contrast, transfused RBCs with the KEL glycoprotein antigen fully intact continued to circulate for days in double-KO mice despite treatment with immunoprophylaxis. Further, in vitro phagocytosis assays showed no consumption of opsonized murine RBCs by double-KO splenocytes. Taken in combination, our data suggest that modulation of the KEL antigen (and potentially RBC clearance) by redundant recipient pathways involving both FcgRs and C3 may be critical to the mechanism of action of polyclonal anti-KEL immunoprophylaxis. These findings could have implications for the development of immunoprophylaxis programs in humans. (Blood. 2016;128(26):3159-3168)
Summary Classical Hodgkin lymphoma (HL) exhibits a bi‐modal age distribution that suggests an infectious aetiology. However, most cases of nodular sclerosis HL (NSHL) are Epstein–Barr virus (EBV) negative (60–90%). Previous studies regarding human herpesvirus 6 (HHV‐6) positivity of HL have led to conflicting results. In order to clarify this situation, we examined NSHL biopsies for the presence and distribution of HHV‐6 by immunohistochemistry (IHC), polymerase chain reaction (PCR), and fluorescence in situ hybridization (FISH). PCR identified HHV‐6 DNA in 86% of NSHL cases. As HHV‐6 DNA was also identified in most cases of reactive lymphoid hyperplasia, we sought to localize the virus to specific cells by IHC, which detected HHV‐6 in Reed–Sternberg (RS) cells of nearly half (48%) of NSHL cases. Dual CD30/HHV‐6 immunostaining confirmed HHV‐6 immunoreactivity in CD30+ RS cells, and HHV‐6 PCR positivity was confirmed in laser capture microdissection‐isolated CD30+ RS cells. FISH demonstrated multiple copies of HHV‐6 genome in scattered cells. In contrast, EBV+ RS cells were identified in only 24% of the cases. HHV‐6+ cases trended toward a younger age than EBV+ cases. These results conclusively demonstrate that RS cells in many cases of NSHL are HHV‐6 positive, and suggest that HHV‐6 may play a role in NSHL pathogenesis, particularly in younger patients with EBV‐negative disease.
Background:The rapid acquisition of biological data and development of computationally intensive analyses has led to a need for novel approaches to software deployment. In particular, the complexity of common analytic tools for genomics makes them difficult to deploy and decreases the reproducibility of computational experiments.Methods:Recent technologies that allow for application virtualization, such as Docker, allow developers and bioinformaticians to isolate these applications and deploy secure, scalable platforms that have the potential to dramatically increase the efficiency of big data processing.Results:While limitations exist, this study demonstrates a successful implementation of a pipeline with several discrete software applications for the analysis of next-generation sequencing (NGS) data.Conclusions:With this approach, we significantly reduced the amount of time needed to perform clonal analysis from NGS data in acute myeloid leukemia.
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