Characterization of Human B Cell Hematological Malignancies Using Protein-Based Approaches.

The maturation of B cells is a complex, multi-step process. During B cell differentiation, errors can occur, leading to the emergence of aberrant versions of B cells that, finally, constitute a malignant tumor. These B cell malignancies are classified into three main groups: leukemias, myelomas, and lymphomas, the latter being the most heterogeneous type. Since their discovery, multiple biological studies have been performed to characterize these diseases, aiming to define their specific features and determine potential biomarkers for diagnosis, stratification, and prognosis. The rise of advanced -omics approaches has significantly contributed to this end. Notably, proteomics strategies appear as promising tools to comprehensively profile the final molecular effector of these cells. In this narrative review, we first introduce the main B cell malignancies together with the most relevant proteomics approaches. Then, we describe the core studies conducted in the field and their main findings and, finally, we evaluate the advantages and drawbacks of flow cytometry, mass cytometry, and mass spectrometry for the profiling of human B cell disorders.

A Case of Blastic Plasmacytoid Dendritic Cell Neoplasm with Orbital Tumor as the Initial Symptom.

BACKGROUND: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy arising from precursor dendritic cells. It is a rare and challenging clinical presentation. For decades, there has been no treatment course for managing BPDCN and its overall prognosis is poor. METHODS AND RESULTS: We report a 27-year-old man who was admitted to the hospital due to an orbital tumor as the first symptom. Progressive enlargement of the orbital tumor was accompanied by multiple purple circular nodules on the body trunk. Pathological confirmation of BPDCN after resection of the orbital mass. Bone marrow smear and flow cytometry on examination indicate AML-M5. Performance of chemotherapy and peripheral blood autologous stem cell transplantation. CONCLUSIONS: The clinical manifestations of blastic plasmacytoid dendritic cell neoplasms are diverse. The diagnosis of BPDCN can be difficult due to overlapping morphologic, immunophenotypic, and clinical features of other hematologic AML. Relapsed and refractory BPDCN remains an elusive therapeutic challenge. The future of new targeted therapeutic drugs is expected.

Non-invasive prenatal test identifies circulating cell-free DNA chromosomal abnormalities derived from clonal hematopoiesis in aggressive hematological malignancies.

Liquid biopsy is a minimally invasive diagnostic tool for identification of tumor-related mutations in circulating cell-free DNA (cfDNA). The aim of this study was to investigate feasibility, sensitivity, and specificity of non-invasive prenatal test (NIPT) for identification of chromosomal abnormalities in cfDNA from a total of 77 consecutive patients with non-Hodgkin B-cell lymphomas, Hodgkin lymphoma (HL), or plasma cell dyscrasia. In this case series, half of patients had at least one alteration, more frequently in chromosome 6 (23.1%), chromosome 9 (20.5%), and chromosomes 3 and 18 (16.7%), with losses of chromosome 6 and gains of chromosome 7 negatively impacting on overall survival (OS), with a 5-year OS of 26.9% and a median OS of 14.6 months, respectively (P = 0.0009 and P = 0.0004). Moreover, B-cell lymphomas had the highest NIPT positivity, especially those with aggressive lymphomas, while patients with plasma cell dyscrasia with extramedullary disease had a higher NIPT positivity compared to conventional cytogenetics analysis and a worse outcome. Therefore, we proposed a NIPT-based liquid biopsy a complementary minimally invasive tool for chromosomal abnormality detection in hematological malignancies. However, prospective studies on larger cohorts are needed to validate clinical utility of NIPT-based liquid biopsy in routinely clinical practice.

Hematologic cancer diagnosis and classification using machine and deep learning: State-of-the-art techniques and emerging research directives.

Hematology is the study of diagnosis and treatment options for blood diseases, including cancer. Cancer is considered one of the deadliest diseases across all age categories. Diagnosing such a deadly disease at the initial stage is essential to cure the disease. Hematologists and pathologists rely on microscopic evaluation of blood or bone marrow smear images to diagnose blood-related ailments. The abundance of overlapping cells, cells of varying densities among platelets, non-illumination levels, and the amount of red and white blood cells make it more difficult to diagnose illness using blood cell images. Pathologists are required to put more effort into the traditional, time-consuming system. Nowadays, it becomes possible with machine learning and deep learning techniques, to automate the diagnostic processes, categorize microscopic blood cells, and improve the accuracy of the procedure and its speed as the models developed using these methods may guide an assisting tool. In this article, we have acquired, analyzed, scrutinized, and finally selected around 57 research papers from various machine learning and deep learning methodologies that have been employed in the diagnosis of leukemia and its classification over the past 20 years, which have been published between the years 2003 and 2023 by PubMed, IEEE, Science Direct, Google Scholar and other pertinent sources. Our primary emphasis is on evaluating the advantages and limitations of analogous research endeavors to provide a concise and valuable research directive that can be of significant utility to fellow researchers in the field.

Evaluation of the pathogenic potential of germline DDX41 variants in hematopoietic neoplasms using the ACMG/AMP guidelines.

Clinical use of gene panel testing for hematopoietic neoplasms in areas, such as diagnosis, prognosis prediction, and exploration of treatment options, has increased in recent years. The keys to interpreting gene variants detected in gene panel testing are to distinguish between germline and somatic variants and accurately determine whether the detected variants are pathogenic. If a variant is suspected to be a pathogenic germline variant, it is essential to confirm its consistency with the disease phenotype and gather a thorough family history. Donor eligibility must also be considered, especially if the patient's variant is also detected in the expected donor for hematopoietic stem cell transplantation. However, determining the pathogenicity of gene variants is often complicated, given the current limited availability of databases covering germline variants of hematopoietic neoplasms. This means that hematologists will frequently need to interpret gene variants themselves. Here, we outline how to assess the pathogenicity of germline variants according to criteria from the American College of Medical Genetics and Genomics/Association for Molecular Pathology standards and guidelines for the interpretation of variants using DDX41, a gene recently shown to be closely associated with myeloid neoplasms with a germline predisposition, as an example.

The landscape of cytogenetic and molecular genetic methods in diagnostics for hematologic neoplasia.

Improvements made during the last decades in the management of patients with hematologic neoplasia have resulted in increase of overall survival. These advancements have become possible through progress in our understanding of genetic basis of different hematologic malignancies and their role in the current risk-adapted treatment protocols. In this review, we provide an overview of current cytogenetic and molecular genetic methods, commonly used in the genetic characterization of hematologic malignancies, describe the current developments in the cytogenetic and molecular diagnostics, and give an outlook into their future development. Furthermore, we give a brief overview of the most important public databases and guidelines for sequence variant interpretation.

Hairy cell leukemia 2024: Update on diagnosis, risk-stratification, and treatment-Annual updates in hematological malignancies.

DISEASE OVERVIEW: Hairy cell leukemia (HCL) and HCL-like disorders, including HCL variant (HCL-V) and splenic diffuse red pulp lymphoma (SDRPL), are a very heterogenous group of mature lymphoid B-cell disorders characterized by the identification of hairy cells, a specific genetic profile, a different clinical course and the need for appropriate treatment. DIAGNOSIS: Diagnosis of HCL is based on morphological evidence of hairy cells, an HCL immunologic score of 3 or 4 based on the CD11c, CD103, CD123, and CD25 expression, the trephine biopsy which makes it possible to specify the degree of tumoral bone marrow infiltration and the presence of BRAFV600E somatic mutation. RISK STRATIFICATION: Progression of patients with HCL is based on a large splenomegaly, leukocytosis, a high number of hairy cells in the peripheral blood, and the immunoglobulin heavy chain variable region gene mutational status. VH4-34 positive HCL cases are associated with a poor prognosis, as well as HCL with TP53 mutations and HCL-V. TREATMENT: Patients should be treated only if HCL is symptomatic. Chemotherapy with risk-adapted therapy purine analogs (PNAs) are indicated in first-line HCL patients. The use of chemo-immunotherapy combining cladribine (CDA) and rituximab (R) represents an increasingly used therapeutic approach. Management of relapsed/refractory disease is based on the use of BRAF inhibitors (BRAFi) plus R, MEK inhibitors (MEKi), recombinant immunoconjugates targeting CD22, Bruton tyrosine kinase inhibitors (BTKi), and Bcl-2 inhibitors (Bcl-2i). However, the optimal sequence of the different treatments remains to be determined.

A novel method for simultaneous detection of hematological tumors and infectious pathogens by metagenomic next generation sequencing of plasma.

BACKGROUND: Metagenomic next-generation sequencing (mNGS) is valuable for pathogen identification; however, distinguishing between infectious diseases and conditions with potentially similar clinical manifestations, including malignant tumors, is challenging. Therefore, we developed a method for simultaneous detection of infectious pathogens and cancer in blood samples. METHODS: Plasma samples (n = 244) were collected from 150 and 94 patients with infections and hematological malignancies, respectively, and analyzed by mNGS for pathogen detection, alongside human tumor chromosomal copy number variation (CNV) analysis (≥5Mbp or 10Mbp CNV region). Further, an evaluation set, comprising 87 plasma samples, was analyzed by mNGS and human CNV analysis, to validate the feasibility of the method. RESULTS: Among 94 patients with hematological malignancy, sensitivity values of CNV detection for tumor diagnosis were 69.15 % and 32.98 % for CNV region 5Mbp and 10Mbp, respectively, with corresponding specificities of 92.62 % and 100 % in the infection group. Area under the ROC curve (AUC) values for 5Mbp and 10Mbp region were 0.825 and 0.665, respectively, which was a significant difference of 0.160 (95 % CI: 0.110-0.210; p < 0.001), highlighting the superiority of 5Mbp output region data. Six patients with high-risk CNV results were identified in the validation study: three with history of tumor treatment, two eventually newly-diagnosed with hematological malignancies, and one with indeterminate final diagnosis. CONCLUSIONS: Concurrent CNV analysis alongside mNGS for infection diagnosis is promising for detecting malignant tumors. We recommend adopting a CNV region of 10Mbp over 5Mbp for our model, because of the lower false-positive rate (FPR).

Application of droplet digital PCR in minimal residual disease monitoring of rare fusion transcripts and mutations in haematological malignancies.

Leukaemia of various subtypes are driven by distinct chromosomal rearrangement or genetic abnormalities. The leukaemogenic fusion transcripts or genetic mutations serve as molecular markers for minimal residual disease (MRD) monitoring. The current study evaluated the applicability of several droplet digital PCR assays for the detection of these targets at RNA and DNA levels (atypical BCR::ABL1 e19a2, e23a2ins52, e13a2ins74, rare types of CBFB::MYH11 (G and I), PCM1::JAK2, KMT2A::ELL2, PICALM::MLLT10 fusion transcripts and CEBPA frame-shift and insertion/duplication mutations) with high sensitivity. The analytical performances were assessed by the limit of blanks, limit of detection, limit of quantification and linear regression. Our data demonstrated serial MRD monitoring for patients at molecular level could become "digitalized", which was deemed important to guide clinicians in treatment decision for better patient care.

Treatment of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN): focus on the use of tagraxofusp and clinical considerations.

BPDCN is an aggressive myeloid malignancy with a poor prognosis. It derives from the precursors of plasmacytoid dendritic cells and is characterized by CD123 overexpression, which is seen in all patients with BPDCN. The CD123-directed therapy tagraxofusp is the only approved treatment for BPDCN; it was approved in the US as monotherapy for the treatment of patients aged ≥2 years with treatment-naive or relapsed/refractory BPDCN. Herein, we review the available data supporting the utility of tagraxofusp in treating patients with BPDCN. In addition, we present best practices and real-world insights from clinicians in academic and community settings in the US on how they use tagraxofusp to treat BPDCN. Several case studies illustrate the efficacy of tagraxofusp and discuss its safety profile, as well as the prevention, mitigation, and management of anticipated adverse events.

Liquid biopsy-based circulating tumour (ct)DNA analysis of a spectrum of myeloid and lymphoid malignancies yields clinically actionable results.

AIMS: Liquid biopsy (LBx)-based next-generation sequencing (NGS) of circulating tumour DNA (ctDNA) can facilitate molecular profiling of haematopoietic neoplasms (HNs), particularly when tissue-based NGS is infeasible. METHODS AND RESULTS: We studied HN LBx samples tested with FoundationOne Liquid CDx, FoundationOne Liquid, or FoundationACT between July 2016 and March 2022. We identified 271 samples: 89 non-Hodgkin lymphoma (NHL), 43 plasma-cell neoplasm (PCN), 41 histiocytoses, 27 myelodysplastic syndrome (MDS), 25 diffuse large B-cell lymphoma (DLBCL), 22 myeloproliferative neoplasm (MPN), 14 Hodgkin lymphoma (HL), and 10 acute myeloid leukaemia (AML). Among 73.4% with detectable pathogenic alterations, median maximum somatic allele frequency (MSAF) was 16.6%, with AML (36.2%), MDS (19.7%), and MPN (44.5%) having higher MSAFs than DLBCL (3.9%), NHL (8.4%), HL (1.5%), PCN (2.8%), and histiocytoses (1.8%) (P = 0.001). LBx detected characteristic alterations across HNs, including in TP53, KRAS, MYD88, and BTK in NHLs; TP53, KRAS, NRAS, and BRAF in PCNs; IGH in DLBCL; TP53, ATM, and PDCD1LG2 in HL; BRAF and MAP2K1 in histiocytoses; TP53, SF3B1, DNMT3A, TET2, and ASXL1 in MDS; JAK2 in MPNs; and FLT3, IDH2, and NPM1 in AML. Among 24 samples, the positive percent agreement by LBx was 75.7% for variants present in paired buffy coat, marrow, or tissues. Also, 75.0% of pairs exhibited alterations only present on LBx. These were predominantly subclonal (clonal fraction of 3.8%), reflecting the analytical sensitivity of LBx. CONCLUSION: These data demonstrate that LBx can detect relevant genomic alterations across HNs, including at low clonal fractions, suggesting a potential clinical utility for identifying residual or emerging therapy-resistant clones that may be undetectable in site-specific tissue biopsies.

Aptamer-Based Multiparameter Analysis for Molecular Profiling of Hematological Malignancies.

The subtypes of hematological malignancies (HM) with minimal molecular profile differences display an extremely heterogeneous clinical course and a discrepant response to certain treatment regimens. Profiling the surface protein markers offers a potent solution for precision diagnosis of HM by differentiating among the subtypes of cancer cells. Herein, we report the use of Cell-SELEX technology to generate a panel of high-affinity aptamer probes that are able to discriminate subtle differences among surface protein profiles between different HM cells. Experimental results show that these aptamers with apparent dissociation constants (Kd) below 10 nM display a unique recognition pattern on different HM subtypes. By combining a machine learning model on the basis of partial least-squares discriminant analysis, 100% accuracy was achieved for the classification of different HM cells. Furthermore, we preliminarily validated the effectiveness of the aptamer-based multiparameter analysis strategy from a clinical perspective by accurately classifying complex clinical samples, thus providing a promising molecular tool for precise HM phenotyping.

Detección incidental de niveles de vitamina B12 elevados y su relación con neoplasias / Incidental detection of raised serum levels of vitaminB12 and its association with neoplasms

Antecedentes y objetivo Los niveles elevados de vitaminaB12 se han asociado a enfermedades oncohematológicas. Sin embargo, se desconoce la relevancia de su detección incidental en sujetos sin un diagnóstico previo de cáncer. El objetivo de este estudio es evaluar la relación de la hipercobalaminemia y el diagnóstico de un proceso tumoral y establecer los factores de riesgo. Material y métodos Estudio observacional retrospectivo de una cohorte de pacientes con hipercobalaminemia. Se comparó la incidencia de neoplasias con una cohorte de pacientes con vitaminaB12<1.000pg/ml. Resultados Se seleccionaron 4.800 sujetos con determinaciones de vitaminaB12: 345 (7,1%) presentaban niveles >1.000pg/ml. Se excluyeron 68 (28,4%) por administración exógena, 12 (5%) por datos insuficientes y 15 (3%) por una neoplasia activa, seleccionando 250 pacientes; mediana de seguimiento: 22 (RIQ: 12-39) meses. Se detectó: hepatopatía 59 (23,6%), 44 (18,2%) presentaron cáncer de órgano sólido y 17 (7,1%), hemopatía maligna. El tiempo medio desde la detección de hipercobalaminemia al diagnóstico fue de 10meses. La mediana hasta el diagnóstico fue mayor en el grupo de vitaminaB12 elevada (13 vs 51meses; p<0,001). La hipercobalaminemia (HR_ 11,8; IC95: 2,8-49,6; p=0,001) y el tabaquismo (HR: 4,0; IC95%: 2,15-7,59; p<0,001) resultaron predictores independientes. Conclusiones La detección incidental de niveles séricos de vitaminaB12 >1.000pg/ml es elevada. El diagnóstico de neoplasia órgano sólido y hematológica es frecuente durante el año siguiente de seguimiento, siendo la hipercobalaminemia y el tabaquismo factores predictores de un mayor riesgo de cáncer. (AU)

Background and objective Elevated serum levels of vitaminB12 have been associated with oncohematological diseases. However, the relevance of its incidental detection in subjects without a previous diagnosis of cancer is unknown. The aim of this study was to evaluate the relationship between incidental hypercobalaminemia (vitaminB12 >1000pg/mL) and the diagnosis of a tumor process in patients without a diagnosis and to establish the risk factors. Material and methods Retrospective observational study of a cohort of patients with hypercobalaminemia. The incidence of neoplasms was compared with a cohort of patients with vitaminB12 levels <1000pg/mL. Results Vitamin B12 determinations of 4800 subjects were selected. Of them, 345 (7.1%) had levels >1000pg/ml; 68 (28.4%) were excluded due to exogenous administration, 12 (5%) due to insufficient data, and 15 (3%) due to having an active neoplasia, selecting 250 patients, with a median follow-up of 22 (IQR: 12-39) months. Structural liver disease was detected in 59 (23.6%). 18.2% (44 patients) had solid organ cancer and 17 (7.1%) had malignant hemopathy. The average time from the detection of hypercobalaminemia to the diagnosis of cancer was about 10months. The median until the diagnosis of neoplasia was higher in the high vitaminB12 group (13 vs 51months; P<.001). Hypercobalaminemia (HR: 11.8; 95%CI: 2.8-49.6; P=.001) and smoking (HR: 4.0; 95%CI: 2.15-7.59; P<.001) were independent predictors of neoplasia in the multivariate analysis. Conclusions Incidental detection of serum vitaminB12 levels >1000pg/ml is high in the population. The diagnosis of solid organ and hematological neoplasia is frequent during the following year of follow-up, with hypercobalaminemia and smoking being predictors of a higher risk of cancer. (AU)

Detección incidental de niveles de vitamina B12 elevados y su relación con neoplasias / Incidental detection of raised serum levels of vitaminB12 and its association with neoplasms

Antecedentes y objetivo Los niveles elevados de vitaminaB12 se han asociado a enfermedades oncohematológicas. Sin embargo, se desconoce la relevancia de su detección incidental en sujetos sin un diagnóstico previo de cáncer. El objetivo de este estudio es evaluar la relación de la hipercobalaminemia y el diagnóstico de un proceso tumoral y establecer los factores de riesgo. Material y métodos Estudio observacional retrospectivo de una cohorte de pacientes con hipercobalaminemia. Se comparó la incidencia de neoplasias con una cohorte de pacientes con vitaminaB12<1.000pg/ml. Resultados Se seleccionaron 4.800 sujetos con determinaciones de vitaminaB12: 345 (7,1%) presentaban niveles >1.000pg/ml. Se excluyeron 68 (28,4%) por administración exógena, 12 (5%) por datos insuficientes y 15 (3%) por una neoplasia activa, seleccionando 250 pacientes; mediana de seguimiento: 22 (RIQ: 12-39) meses. Se detectó: hepatopatía 59 (23,6%), 44 (18,2%) presentaron cáncer de órgano sólido y 17 (7,1%), hemopatía maligna. El tiempo medio desde la detección de hipercobalaminemia al diagnóstico fue de 10meses. La mediana hasta el diagnóstico fue mayor en el grupo de vitaminaB12 elevada (13 vs 51meses; p<0,001). La hipercobalaminemia (HR_ 11,8; IC95: 2,8-49,6; p=0,001) y el tabaquismo (HR: 4,0; IC95%: 2,15-7,59; p<0,001) resultaron predictores independientes. Conclusiones La detección incidental de niveles séricos de vitaminaB12 >1.000pg/ml es elevada. El diagnóstico de neoplasia órgano sólido y hematológica es frecuente durante el año siguiente de seguimiento, siendo la hipercobalaminemia y el tabaquismo factores predictores de un mayor riesgo de cáncer. (AU)

Background and objective Elevated serum levels of vitaminB12 have been associated with oncohematological diseases. However, the relevance of its incidental detection in subjects without a previous diagnosis of cancer is unknown. The aim of this study was to evaluate the relationship between incidental hypercobalaminemia (vitaminB12 >1000pg/mL) and the diagnosis of a tumor process in patients without a diagnosis and to establish the risk factors. Material and methods Retrospective observational study of a cohort of patients with hypercobalaminemia. The incidence of neoplasms was compared with a cohort of patients with vitaminB12 levels <1000pg/mL. Results Vitamin B12 determinations of 4800 subjects were selected. Of them, 345 (7.1%) had levels >1000pg/ml; 68 (28.4%) were excluded due to exogenous administration, 12 (5%) due to insufficient data, and 15 (3%) due to having an active neoplasia, selecting 250 patients, with a median follow-up of 22 (IQR: 12-39) months. Structural liver disease was detected in 59 (23.6%). 18.2% (44 patients) had solid organ cancer and 17 (7.1%) had malignant hemopathy. The average time from the detection of hypercobalaminemia to the diagnosis of cancer was about 10months. The median until the diagnosis of neoplasia was higher in the high vitaminB12 group (13 vs 51months; P<.001). Hypercobalaminemia (HR: 11.8; 95%CI: 2.8-49.6; P=.001) and smoking (HR: 4.0; 95%CI: 2.15-7.59; P<.001) were independent predictors of neoplasia in the multivariate analysis. Conclusions Incidental detection of serum vitaminB12 levels >1000pg/ml is high in the population. The diagnosis of solid organ and hematological neoplasia is frequent during the following year of follow-up, with hypercobalaminemia and smoking being predictors of a higher risk of cancer. (AU)

Performance comparison of two automated digital morphology analyzers for leukocyte differential in patients with malignant hematological diseases: Mindray MC-80 and Sysmex DI-60.

BACKGROUND: The MC-80 (Mindray, Shenzhen, China), a newly available artificial intelligence (AI)-based digital morphology analyzer, is the focus of this study. We aim to compare the leukocyte differential performance of the Mindray MC-80 with that of the Sysmex DI-60 and the gold standard, manual microscopy. METHODS: A total of 100 abnormal peripheral blood (PB) smears were compared across the MC-80, DI-60, and manual microscopy. Sensitivity, specificity, predictive value, and efficiency were calculated according to the Clinical and Laboratory Standards Institute (CLSI) EP12-A2 guidelines. Comparisons were made using Bland-Altman analysis and Passing-Bablok regression analysis. Additionally, within-run imprecision was evaluated using five samples, each with varying percentages of mature leukocytes and blasts, in accordance with CLSI EP05-A3 guidelines. RESULTS: The within-run coefficient of variation (%CV) of the MC-80 for most cell classes in the five samples was lower than that of the DI-60. Sensitivities for the MC-80 ranged from 98.2% for nucleated red blood cells (NRBC) to 28.6% for reactive lymphocytes. The DI-60's sensitivities varied between 100% for basophils and reactive lymphocytes, and 11.1% for metamyelocytes. Both analyzers demonstrated high specificity, negative predictive value, and efficiency, with over 90% for most cell classes. However, the DI-60 showed relatively lower specificity for lymphocytes (73.2%) and lower efficiency for blasts and lymphocytes (80.1% and 78.6%, respectively) compared with the MC-80. Bland-Altman analysis indicated that the absolute mean differences (%) ranged from 0.01 to 4.57 in MC-80 versus manual differential and 0.01 to 3.39 in DI-60 versus manual differential. After verification by technicians, both analyzers exhibited a very high correlation (r = 0.90-1.00) with the manual differential results in neutrophils, lymphocytes, and blasts. CONCLUSIONS: The Mindray MC-80 demonstrated good performance for leukocyte differential in PB smears, notably exhibiting higher sensitivity for blasts identification than the DI-60.

Disparity in hematological malignancies: From patients to health care professionals.

In the recent few decades, outcomes in patients diagnosed with hematological malignancies have been steadily improving. However, the improved prognosis does not distribute equally among patients from different backgrounds. Besides cancer biology, demographic and geographic disparities have been found to impact overall survival significantly. Specifically, patients from underrepresented minorities including Black and Hispanics, and those with uninsured status, having low socioeconomic status, or from rural areas have had worse outcomes historically, which is uniformly true across all major subtypes of hematological malignancies. Similar discrepancy is also seen in the health care professional field, where a gender gap and a disproportionally low representation of health care providers from underrepresented minorities have been long existing. Thus, a comprehensive strategy to mitigate disparity in the health care system is needed to achieve equity in health care.

Diagnostic management of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in close interaction with therapeutic considerations.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare malignancy derived from plasmacytoid dendritic cells, can mimic both acute leukemia and aggressive T-cell lymphoma. Therapy of this highly aggressive hematological disease should be initiated as soon as possible, especially in light of novel targeted therapies that have become available. However, differential diagnosis of BPDCN remains challenging. This retrospective study aimed to highlight the challenges to timely diagnoses of BPDCN. We documented the diagnostic and clinical features of 43 BPDCN patients diagnosed at five academic hospitals from 2001-2022. The frequency of BPDCN diagnosis compared to AML was 1:197 cases. The median interval from the first documented clinical manifestation to diagnosis of BPDCN was 3 months. Skin (65%) followed by bone marrow (51%) and blood (45%) involvement represented the most common sites. Immunophenotyping revealed CD4 + , CD45 + , CD56 + , CD123 + , HLA-DR + , and TCL-1 + as the most common surface markers. Overall, 86% (e.g. CD33) and 83% (e.g., CD7) showed co-expression of myeloid and T-cell markers, respectively. In the median, we detected five genomic alterations per case including mutational subtypes typically involved in AML: DNA methylation (70%), signal transduction (46%), splicing factors (38%), chromatin modification (32%), transcription factors (32%), and RAS pathway (30%), respectively. The contribution of patients (30%) proceeding to any form of upfront stem cell transplantation (SCT; autologous or allogeneic) was almost equal resulting in beneficial overall survival rates in those undergoing allogeneic SCT (p = 0.0001). BPDCN is a rare and challenging entity sharing various typical characteristics of other hematological diseases. Comprehensive diagnostics should be initiated timely to ensure appropriate treatment strategies.

A framework for the clinical implementation of optical genome mapping in hematologic malignancies.

Optical Genome Mapping (OGM) is rapidly emerging as an exciting cytogenomic technology both for research and clinical purposes. In the last 2 years alone, multiple studies have demonstrated that OGM not only matches the diagnostic scope of conventional standard of care cytogenomic clinical testing but it also adds significant new information in certain cases. Since OGM consolidates the diagnostic benefits of multiple costly and laborious tests (e.g., karyotyping, fluorescence in situ hybridization, and chromosomal microarrays) in a single cost-effective assay, many clinical laboratories have started to consider utilizing OGM. In 2021, an international working group of early adopters of OGM who are experienced with routine clinical cytogenomic testing in patients with hematological neoplasms formed a consortium (International Consortium for OGM in Hematologic Malignancies, henceforth "the Consortium") to create a consensus framework for implementation of OGM in a clinical setting. The focus of the Consortium is to provide guidance for laboratories implementing OGM in three specific areas: validation, quality control and analysis and interpretation of variants. Since OGM is a complex technology with many variables, we felt that by consolidating our collective experience, we could provide a practical and useful tool for uniform implementation of OGM in hematologic malignancies with the ultimate goal of achieving globally accepted standards.