EJHaem最新文献

Introduction

Acute myeloid leukemia (AML) remains one of the deadliest hematopoietic malignancies. A better understanding of the molecular biology governing AML may lead to improved risk stratification and facilitate the development of novel therapies. Proteins are responsible for much of the biology of cells. Several studies have examined the global proteome in bulk mononuclear cells (MNCs) from AML specimens, which are comprised a heterogenous population of cells at various stages of differentiation.

Methods

Given the potential impact of the nonleukemic cells on protein expression profiles, we applied an integrative proteogenomic approach utilizing next-generation sequencing and mass spectrometry-based proteomics to identify novel protein biomarkers in unsorted MNCs and viable leukemic blasts (VLBs) isolated from blood and bone marrow specimens obtained at the time of AML diagnosis.

Results

We identified significant differences in protein expression between VLBs and MNCs. Subsequent studies (N = 27) focused on proteomic profiling of VLBs that identified novel candidate biomarkers associated with mutational genotypes and clinical outcome, some of which were recapitulated in an independent cohort of patients. Using mass spectrometry, we also detected mutated protein products, some of which were predicted via in silico analyses to be potential neoantigens amenable to adoptive immunotherapy. As previously described, analyses comparing transcript and protein expression showed an overall modest correlation between mRNA and protein dataset, but enriching for genes associated with mutations significantly improved the protein–RNA correlation.

Conclusion

Together, the results provide insight into the biology of VLBs and demonstrate the gains derived from examining the proteome in addition to genome and transcriptome.

Introduction

Multiple myeloma (MM) is a relapsing, debilitating blood cancer which remains incurable despite advances in treatments. Patients typically receive multiple lines of treatment, to which they become refractory, thereby limiting treatment options. B-cell maturation antigen (BCMA) bispecific antibodies (BsAbs) represent a novel modality of treatment that has significant efficacy for relapsed or refractory patients.

The objective was to develop consensus statements for the effective implementation of BCMA BsAbs for relapsed or refractory MM patients within the National Health Service (NHS).

Methods

The process employed a modified Delphi methodology. In March 2023, a literature review on the topic of novel treatments for MM was performed using the PubMed database.

The process employed a modified Delphi methodology. Following a literature review, a steering group of eight expert clinicians identified and agreed on five main topics of focus and 44 statements. These were then developed into an online survey which was distributed to healthcare professionals working in Levels 1, 2 and 3 haematology centres in the United Kingdom. Results were then shared with the expert panel to determine conclusions. The threshold for consensus agreement was set at 75%.

Results

A total of 60 responses were received from all three centre levels. There was representation from all targeted centres. Consensus was achieved in 42 statements (95%) across three broad areas: the patient profile, initiation and step-up dosing, monitoring and ongoing care, the role of multidisciplinary team and service designs for optimal management, consensus was not achieved for two statements. Given the level of agreement and that the stopping criteria were met, it was decided not to undertake further Delphi rounds.

Conclusion

This consensus provides a framework to support the effective introduction of novel treatments for MM in the NHS. The results were used to inform a checklist for use within haematology services when considering the provision of MM care specific to BCMA BsAbs.

Introduction

Myeloid neoplasms (MNs) frequently harbor pathogenic mutations not detected by karyotyping and fluorescence in situ hybridization; hence, next-generation sequencing (NGS) is necessary for diagnosis, risk stratification, and therapy. If, however, NGS is not clinically indicated but still performed, the results may promote futile avenues of investigation, heighten patient distress, and increase cost.

Methods

We created criteria to approve NGS testing for MN (MN-NGS) with the goal of maximizing actionable results. These actionable results include making a new MN diagnosis, characterizing a MN with baseline mutational status, and altering treatment plans. Approval criteria included clinical suspicion of new, relapsed, or worsening disease and end-of-induction chemotherapy. Cancellation criteria included the suspicion of non-myeloid disease only, no suspicion of progression of a known MN, no evidence for recurrence post-transplant, a diagnosis of chronic myeloid leukemia, and cases using blood when a concurrent bone marrow NGS is being performed. We applied these criteria to NGS tests ordered at our institution between August and December 2018 and determined whether any tests meeting our cancelation criteria yielded actionable results.

Results

Consecutive MN-NGS orders (n = 174) were retrospectively categorized as appropriate (Group A, n = 115), inappropriate (Group B, n = 29), and appropriately canceled (group C, n = 30). Seventy-five of the 115 (65%) Group A tests and none of the 29 (0%) Group B tests yielded actionable results (p < 0.0001).

Conclusion

Approximately one third (59/174) of MN-NGS test orders can be safely canceled using these criteria, which would result in $150,370 of Centers for Medicare and Medicaid Services-reimbursed savings annually.

Introduction

Castleman disease (CD) represents a spectrum of heterogeneous lymphoproliferative disorders sharing peculiar histopathological features, clinically subdivided into unicentric CD (UCD) and multicentric CD (MCD) and presenting with variable inflammatory symptoms. Interleukin (IL)-6 and other cytokines play a major role in mediating CD inflammatory manifestations. Although the local microenvironment seems to be among the major sources of hypercytokinemia, the precise cellular origin of IL-6 production in CD is still debated.

Methods

A series of five nodal CD of different subtypes (one UCD, two idiopathic MCDs [iMCDs], one HIV-negative human herpesvirus 8 (HHV8)-associated MCD, and one HIV-positive HHV8-associated MCD) and a non-CD reactive control were tested using RNAscope analysis and a dual in situ hybridization (ISH)/immunohistochemistry technique, in order to quantify IL-6 expression and its spatial distribution. Quantitative analyses of in situ mRNA were performed on digitalized slides using the HISTOQUANT software (3DHISTECH) and differences between cases were evaluated by the Kruskal-Wallis test.

Results

RNA-ISH documented increased IL-6 expression in all CD lymph nodes, independently from clinical and pathological subtypes, however, the highest levels were found in HHV8+ cases and statistically significant differences in IL-6 expression were found only between HHV8+ MCD and control case. Dual RNA-ISH for IL6 coupled with immunohistochemistry analysis showed that IL-6 was overexpressed in CD31-positive endothelial cells in 5/5 CD tested cases but not in the control case.

Conclusion

Our findings suggest that nodal IL-6 expression seems to be significantly upregulated in HHV8+ MCD, but a trend toward increased nodal IL-6 expression was noticed also in UCD and iMCD-not otherwise specified. CD31+ endothelial cells probably represent one of the major sources of IL-6 production in the nodal microenvironment.

Background

Acute myeloid leukaemia (AML) is an aggressive and heterogeneous malignant disease. Patient age, comorbidities and disease-specific genetic abnormalities are recognized as primary determinants of treatment response. Recent years have elucidated the significance of nutritional status and inflammation across various malignancies, including AML, in influencing treatment outcomes.

Aims

To assess the prognostic value of the C-reactive protein-albumin ratio (CAR) and the Glasgow Prognostic Score (GPS) in predicting overall survival (OS) rates among patients diagnosed with AML.

Material and methods

189 AML patients receiving standard cytarabine and anthracycline-based induction treatment were included. Baseline demographic, clinical and laboratory data were collected, and treatment outcomes and survival were registered for all patients.

Results

No significant association between CAR and prognosis among AML patients was found, even in subgroup analyses. Hypoalbuminemia was an independent predictor of poor survival among all patients (OS 28 vs. 16 months; p < 0.02). Patients with a GPS of 0 or 1 demonstrated superior OS compared to those with a GPS of 2 (median OS 28 vs. 16 months, respectively; p = 0.015). Results remained consistent among patients ≥ 60 years (median OS 15 vs. 6 months; p = 0.020).

Conclusion

Heightened inflammation and suboptimal nutritional status correlate with unfavourable prognoses in AML patients. Such insights hold the potential for guiding clinical decision-making, offering easily accessible prognostic information for the induction treatment of eligible AML patients.