40 research outputs found
A common founding clone with TP53 and PTEN mutations gives rise to a concurrent germ cell tumor and acute megakaryoblastic leukemia
We report the findings from a patient who presented with a concurrent mediastinal germ cell tumor (GCT) and acute myeloid leukemia (AML). Bone marrow pathology was consistent with a diagnosis of acute megakaryoblastic leukemia (AML M7), and biopsy of an anterior mediastinal mass was consistent with a nonseminomatous GCT. Prior studies have described associations between hematological malignancies, including AML M7 and nonseminomatous GCTs, and it was recently suggested that a common founding clone initiated both cancers. We performed enhanced exome sequencing on the GCT and the AML M7 from our patient to define the clonal relationship between the two cancers. We found that both samples contained somatic mutations in PTEN (C136R missense) and TP53 (R213 frameshift). The mutations in PTEN and TP53 were present at ā¼100% variant allele frequency (VAF) in both tumors. In addition, we detected and validated five other shared somatic mutations. The copy-number analysis of the AML exome data revealed an amplification of Chromosome 12p. We also identified a heterozygous germline variant in FANCA (S858R), which is known to be associated with Fanconi anemia but is of uncertain significance here. In summary, our data not only support a common founding clone for these cancers but also suggest that a specific set of distinct genomic alterations (in PTEN and TP53) underlies the rare association between GCT and AML. This association is likely linked to the treatment resistance and extremely poor outcome of these patients. We cannot resolve the clonal evolution of these tumors given limitations of our data
Impact of sarcopenia on treatment tolerance in United States veterans with diffuse large Bācell lymphoma treated with CHOPābased chemotherapy
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134181/1/ajh24465_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134181/2/ajh24465.pd
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<i>Trans</i>-vaccenic acid reprograms CD8<sup>+</sup> T cells and anti-tumour immunity
Diet-derived nutrients are inextricably linked to human physiology by providing energy and biosynthetic building blocks and by functioning as regulatory molecules. However, the mechanisms by which circulating nutrients in the human body influence specific physiological processes remain largely unknown. Here we use a blood nutrient compound library-based screening approach to demonstrate that dietary trans-vaccenic acid (TVA) directly promotes effector CD8+ T cell function and anti-tumour immunity in vivo. TVA is the predominant form of trans-fatty acids enriched in human milk, but the human body cannot produce TVA endogenously. Circulating TVA in humans is mainly from ruminant-derived foods including beef, lamb and dairy products such as milk and butter, but only around 19% or 12% of dietary TVA is converted to rumenic acid by humans or mice, respectively. Mechanistically, TVA inactivates the cell-surface receptor GPR43, an immunomodulatory G protein-coupled receptor activated by its short-chain fatty acid ligands. TVA thus antagonizes the short-chain fatty acid agonists of GPR43, leading to activation of the cAMPāPKAāCREB axis for enhanced CD8+ T cell function. These findings reveal that diet-derived TVA represents a mechanism for host-extrinsic reprogramming of CD8+ T cells as opposed to the intrahost gut microbiota-derived short-chain fatty acids. TVA thus has translational potential for the treatment of tumours
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Efficacy of checkpoint inhibition after CAR-T failure in aggressive B-cell lymphomas: outcomes from 15 US institutions
Checkpoint inhibitor (CPI) therapy with anti-PD-1 antibodies has been associated with mixed outcomes in small cohorts of patients with relapsed aggressive B-cell lymphomas after CAR-T failure. To define CPI therapy efficacy more definitively in this population, we retrospectively evaluated clinical outcomes in a large cohort of 96 patients with aggressive B-cell lymphomas receiving CPI therapy after CAR-T failure across 15 US academic centers. Most patients (53%) had diffuse large B-cell lymphoma, were treated with axicabtagene ciloleucel (53%), relapsed early (ā¤180 days) after CAR-T (83%), and received pembrolizumab (49%) or nivolumab (43%). CPI therapy was associated with an overall response rate of 19% and a complete response rate of 10%. Median duration of response was 221 days. Median progression-free survival (PFS) and overall survival (OS) were 54 and 159 days, respectively. Outcomes to CPI therapy were significantly improved in patients with primary mediastinal B-cell lymphoma. PFS (128 vs 51 days) and OS (387 vs 131 days) were significantly longer in patients with late (>180 days) vs early (ā¤180 days) relapse after CAR-T. Grade ā„3 adverse events occurred in 19% of patients treated with CPI. Most patients (83%) died, commonly because of progressive disease. Only 5% had durable responses to CPI therapy. In the largest cohort of patients with aggressive B-cell lymphoma treated with CPI therapy after CAR-T relapse, our results reveal poor outcomes, particularly among those relapsing early after CAR-T. In conclusion, CPI therapy is not an effective salvage strategy for most patients after CAR-T, where alternative approaches are needed to improve post-CAR-T outcomes
Expedited evaluation of hereditary hematopoietic malignancies in the setting of stem cell transplantation
Not available
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Infectious complications of car T-cell therapy: A longitudinal risk model
Background: CAR T-cell therapy, where a patient's own T cells are re-engineered to express a receptor to a target of interest, is becoming an increasingly utilized cancer-directed therapy. There are significant toxicities that contribute to a novel state of immunocompromise, leading to new patterns of infectious complications that require further detailed study. Methods: We created a single-center cohort of adult recipients of CD19-directed CAR T-cell therapy and assessed infectious outcomes, supportive care received, toxicities, and markers of immune function up to 2 years following CAR T-cell therapy. Descriptive statistics were used as appropriate for analysis. We additionally conducted time-to-event analysis assessing time-to-first infection with either log-rank testing or Cox regression with univariate analysis, before including significant predictors into a multivariate Cox model of time to infection. Results: We identified 73 patients who received CD19-directed CAR T-cell therapy who predominantly had diffuse large B-cell lymphoma. Within 30 days of cell infusion, bacterial and Candida infections were the most common, with 64% of infections due to these organisms. Between 30 days and 2 years postinfusion, respiratory viruses and pneumonia were the most frequent infections, with 68% of infections due to these etiologies. Receipt of tocilizumab, development of immune effector cell-associated neurotoxicity syndrome (ICANS), or lower neutrophil count were associated with quicker onset of infection in a multivariate Cox model. Conclusions: Respiratory viruses remain an important infectious complication of CAR T-cell therapy following the first year. The model may be a useful tool to identify patients at the highest risk of infection.</p