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AbstractPlasma cell neoplasms (PCN) have infrequently been reported in patients with myelodysplastic syndrome (MDS) and even more rarely in those with myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN). We report the clinicopathologic features of 26 patients with bone marrow myelodysplasia accompanied by PCN, including 21 patients with MDS and 5 with MDS/MPN. The clinicopathologic features of the MDS/MPN-PCN were compared to those of the MDS-PCN group and 68 cases of MDS/MPN without PCN, respectively. The MDS/MPN-PCN group was notable for increased reticulin fibrosis > grade 1 when compared to both the MDS/MPN (p = 0.007) and MDS-PCN (p = 0.02) groups. MDS/MPN-PCN was associated with worse overall survival when compared with MDS-PCN (p = 0.03) and but not with MDS/MPN. Notably, hemoglobin level <8 g/dl (p = 0.008), and IDH2 somatic mutation (p = 0.003) were independent predictors of poor overall survival in all patients with MDS/MPN. Analysis of larger cohorts is required to confirm these associations and provide an insight into the pathogenesis. [ABSTRACT FROM AUTHOR]

Aims: TP53 alterations have a significant prognostic effect in myeloid neoplasms. Our objective was to investigate the TP53 gene mutation status, p53 protein expression and their relationship in dysplasia‐related myeloid neoplasms with varying levels of myeloblast counts. Methods and results: A total of 76 bone marrow biopsy samples with different blast counts were analysed. Total and strong (3+) p53 expression was determined. Dual immunohistochemical staining was performed to determine the cell population associated with p53 expression. NGS analysis was performed using the Accel‐Amplicon Comprehensive TP53 panel. Both p53 expression and TP53 VAF showed a significant correlation with the myeloblast ratio (P < 0.0001); however, p53 expression was also present in other cell lineages. The VAF value exhibited a significant correlation with p53 expression. A high specificity (0.9800) was observed for TP53 mutation using the ≥ 10% strong (3+) p53 cut‐off value, although the sensitivity (0.4231) was low. Conclusions: Strong (3+) p53 expression using a ≥ 10% cut‐off value accurately predicts TP53 mutation but does not reveal the allelic state. The p53 expression is significantly influenced by myeloblast count, and histological interpretation should consider the presence of intermixed non‐neoplastic marrow cells with varying physiological p53 expression. [ABSTRACT FROM AUTHOR]

Summary: The interaction of acute myeloid leukaemic (AML) blasts with the bone marrow (BM) microenvironment is a major determinant governing disease progression and resistance to treatment. The constitutive expression of E‐selectin in the vascular compartment of BM, a key endothelial cell factor, directly mediates chemoresistance via E‐selectin ligand/receptors. Despite the success of hypomethylating agent (HMA)‐containing regimens to induce remissions in older AML patients, the development of primary or secondary resistance is common. We report that following treatment with 5‐azacitidine, promoter regions regulating the biosynthesis of the E‐selectin ligands, sialyl Lewis X, become further hypomethylated. The resultant upregulation of these gene products, in particular α(1,3)‐fucosyltransferase VII (FUT7) and α(2,3)‐sialyltransferase IV (ST3GAL4), likely causes functional E‐selectin binding. When combined with the E‐selectin antagonist uproleselan, the adhesion to E‐selectin is reversed and the survival of mice transplanted with AML cells is prolonged. Finally, we present clinical evidence showing that BM myeloid cells from higher risk MDS and AML patients have the potential to bind E‐selectin, and these cells are more abundant in 5‐azacitidine‐non‐responsive patients. The collective data provide a strong rationale to evaluate 5‐azacitidine in combination with the E‐selectin antagonist, uproleselan, in this patient population. [ABSTRACT FROM AUTHOR]

Primary central nervous system lymphoma (PCNSL) is generally characterized by a poor prognosis and frequent relapsing disease. Consolidation therapy in the upfront setting usually consists of an autologous stem cell transplantation. We report the case of a 19-year-old Caucasian male who had previously undergone an allogeneic stem cell transplantation with complete engraftment for the treatment of juvenile myelomonocytic leukemia when he was 1 year old. He presented with two episodes of (donor-derived) PCNSL from allogeneic stem cells; however, after induction chemotherapy, he failed to harvest stem cells for the consolidation with autologous stem cell transplantation. He was consolidated successfully with a second allogeneic stem cell transplantation with another donor after conditioning with thiotepa, busulfan, and fludarabine. [ABSTRACT FROM AUTHOR]

The role of metalloproteinases (MMPs) in hematological malignancies, like acute myeloid leukemia (AML), myelodysplastic neoplasms (MDS), and multiple myeloma (MM), is well-documented, and these pathologies remain with poor outcomes despite treatment advancements. In this study, we investigated the effects of batimastat (BB-94), an MMP inhibitor (MMPi), in single-administration and daily administration schemes in AML, MDS, and MM cell lines. We used four hematologic neoplasia cell lines: the HL-60 and NB-4 cells as AML models, the F36-P cells as an MDS model, and the H929 cells as a model of MM. We also tested batimastat toxicity in a normal human lymphocyte cell line (IMC cells). BB-94 decreases cell viability and density in a dose-, time-, administration-scheme-, and cell-line-dependent manner, with the AML cells displaying higher responses. The efficacy in inducing apoptosis and cell cycle arrests is dependent on the cell line (higher effects in AML cells), especially with lower daily doses, which may mitigate treatment toxicity. Furthermore, BB-94 activated apoptosis via caspases and ERK1/2 pathways. These findings highlight batimastat's therapeutic potential in hematological malignancies, with daily dosing emerging as a strategy to minimize adverse effects. [ABSTRACT FROM AUTHOR]

Introduction: Chronic Myelomonocytic Leukemia (CMML) and Myelodysplastic Syndromes (MDS) are increasingly represented in the general population. We propose a screening strategy based on algorithms calculated from quantitative and analytical data from the XN analyser. Materials and Methods: We tested the performance of previously published MDS and CMML scores on an evaluation cohort of 749 individual eligible patients over 50 years of age. These patients were classified into 3 groups as follows: 713 patients without MDS or CMML, 18 patients with MDS, and finally 18 patients with CMML. In a second step, a routine cohort of 37 828 samples was studied to evaluate the impact of this approach. Results: The concordance rate between cytology and the two scores is 92.1%. The sensitivity and specificity of the CMML score are 100% and 96.2%, respectively. For the MDS score, they are 83.3% and 89.6% respectively. The ratio of platelets measured by fluorescence on board (PLT‐F) as reflex tests generated is 1.5% after 6 months. The additional smear ratio for suspected MDS is calculated at 0.6%. Conclusion: We propose a flowchart using embedded artificial intelligence to help the cytologist in an optimized smear review and thus improve guidance to the clinician and the patients in the diagnosis process. This strategy permits a more comprehensive approach to MDS and CMML detection fitting with the new definition of CMML according to the recommendations of the World Health Organization (WHO) published in 2022. [ABSTRACT FROM AUTHOR]

Abstract Disease relapse remains a major barrier to success after allogeneic hematopoietic cell transplantation (allo-HCT) in myelodysplastic neoplasms (MDS). While certain high risk genomic alterations are associated with increased risk of relapse, there is a lack of clinically applicable tools to analyze the downstream cellular events that are associated with relapse. We hypothesized that unique proteomic signatures in MDS patients undergoing allo-HCT could serve as a tool to understand this aspect and predict relapse. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we identified 52 MDS patients who underwent allo-HCT and analyzed their proteomic profile from pretransplant blood samples in a matched case-control design. Twenty-six patients without disease relapse after allo-HCT (controls) were matched with 26 patients who experienced relapse (cases). Proteomics assessment was conducted using the Slow Off-rate Modified Aptamers (SOMAmer) based assay. In gene set enrichment analysis, we noted that expression in the hallmark complement, and hallmark allograft rejection pathways were statistically enriched among patients who had disease relapse post-transplant. In addition, correlation analyses showed that methylation array probes in cis- and transcription regulatory elements of immune pathway genes were modulated and differentially sensitize the immune response. These findings suggest that proteomic analysis could serve as a novel tool for prediction of relapse after allo-HCT in MDS.

This article explores the limited understanding and research on myeloid neoplasms, a type of blood cancer, in sub-Saharan Africa, with a focus on Nigeria. It emphasizes the need for more comprehensive studies to gather epidemiological data and improve diagnostic capabilities for these disorders. The authors call for collaboration between healthcare professionals and researchers, as well as increased funding and prioritization of research on myeloid neoplasms in the region. [Extracted from the article]

We report the case of the youngest patient described with VEXAS syndrome associated with MDS-IB1, successfully treated with azacitidine-venetoclax and allogeneic stem cell transplant. [ABSTRACT FROM AUTHOR]

No abstract available. Manuscript truncated after 150 words. HPI: A 55-year-old man presents with a history of cough, poor appetite, low energy, and weight loss over the previous 6-10 months following COVID-19 infection 2 months earlier. PMH, SH, FH: The patient’s past medical history was positive for CVOID-19 infection 2 months earlier as well as pneumonia, not specified, in the previous year. The patient’s past medical history was also remarkable for a 7-unit gastrointestinal hemorrhage approximately one year earlier following polypectomy for benign lesions in the transverse colon. During that hospital admission a complete blood count showed 1% blasts which prompted hematology consultation. The consulting oncologist felt the peripheral blasts were the result of a leukemoid reaction secondary to increased bone marrow stimulation owing to the patient’s acute anemia caused by the gastrointestinal hemorrhage. Macrocytosis and reticulocytosis was also noted and attributed to the same. Repeat complete blood count showed no blasts although some myelocytes, metamyelocytes, and polychromasia …

Objectives: Flow cytometry (FC) is, together with morphology, genetics, and cytogenetics, used in the diagnostic assessment of cytopenia, as its value in evaluating bone marrow dysplasia been highlighted by several studies. However, despite the development of algorithms and guidelines, there is still a lack of standardization of the FC assessment of bone marrow dysplasia. Methods: By combining FC, together with morphological analysis and cytogenetic/molecular assessment in a training cohort of 209 patients, we created a novel score, ProGraME, which includes four parameters, each from a different cell lineage (Progenitor cells, Granulocytes, Monocytes, Erythroid precursors), solely based on relevant population gating. Points for ProGraME were attained for: lymphoid precursors ≤5% of all CD34+ cells (1.5 point); a granulocyte‐to‐lymphocyte side‐scatter ratio ≤6 (1 point); a monocyte CD33‐CV% ≥ 63 (2 points), and an erythroid precursor CD36‐CV% ≥ 65 (2 points). Results: Using a cutoff of ≥2 as suggestive of dysplasia, ProGraME showed a sensitivity of 91% and a specificity of 81% in the training cohort and 95% and 75%, respectively, in an independent validation cohort of 159 patients. In addition, ProGraME had a very high negative predictive value of 97.1% and 97.8% in the training and validation cohorts, respectively, offering a useful tool for excluding bone marrow dysplasia. Finally, among the 23 CCUS patients that scored positive for dysplasia with ProGraME in the training cohort, 16 of them (69%) carried high‐risk mutations, suggesting that FC might help identify early changes of dysplasia. Conclusions: ProGraME can potentially optimize the FC diagnosis of low‐risk myelodysplasia without minimal requirements of flow analysis other than accurate population gating. [ABSTRACT FROM AUTHOR]

RMND1 has been identified as a mitochondriopathy-associated gene less than 12 years ago. The most common phenotype related to this gene is an early onset, severe form of encephalomyopathy that leads to death in a medium time of three years after birth. However, milder and later onset presentations have been reported in some individuals, including two in whom the mitochondriopathy was identified at ~ 40 years of age, and the early onset presentations have been the object of no reports in those who survived beyond age 10. It is thus unclear how lethal RMND1-related conditions really are. We herein describe the oldest case to have been identified hitherto with this condition, i.e., that of a white female who was 61 at the time of diagnosis but was still active in her everyday life. The gene defect identified was nonetheless associated with many manifestations including ovarian insufficiency and sensorineural hearing loss (two features of what is currently designated as Perrault syndrome) as well as chronic renal failure, asymptomatic myopathy, leukopenia, and a few others. In our opinion, this case is of great translational interest for at least three reasons. First, it hints towards the possibility of near-normal life expectancies in some if not many individuals with RMND1 insufficiency. Second, it underlines the wide clinical spectrum associated with this gene. Third, it brings us to question the use of eponyms and syndromic features to identify the true etiology of multisystemic phenotypes. Key messages: RMND1-related conditions typically manifest at an early age with a progressive and lethal form of encephalomyopathy. More benign presentations have been described with some being categorized as Perrault syndrome but none have been diagnosed after the age of 45. The clinical spectrum and presenting age of RMND1-related mitochondriopathies are probably much more varied than implied in the current literature. The case reported in this manuscript illustrates the limitedness of phenotype-based classifications of genetic disorders to identify the defect at cause. [ABSTRACT FROM AUTHOR]

The role of metalloproteinases (MMPs) in hematological malignancies, like acute myeloid leukemia (AML), myelodysplastic neoplasms (MDS), and multiple myeloma (MM), is well-documented, and these pathologies remain with poor outcomes despite treatment advancements. In this study, we investigated the effects of batimastat (BB-94), an MMP inhibitor (MMPi), in single-administration and daily administration schemes in AML, MDS, and MM cell lines. We used four hematologic neoplasia cell lines: the HL-60 and NB-4 cells as AML models, the F36-P cells as an MDS model, and the H929 cells as a model of MM. We also tested batimastat toxicity in a normal human lymphocyte cell line (IMC cells). BB-94 decreases cell viability and density in a dose-, time-, administration-scheme-, and cell-line-dependent manner, with the AML cells displaying higher responses. The efficacy in inducing apoptosis and cell cycle arrests is dependent on the cell line (higher effects in AML cells), especially with lower daily doses, which may mitigate treatment toxicity. Furthermore, BB-94 activated apoptosis via caspases and ERK1/2 pathways. These findings highlight batimastat’s therapeutic potential in hematological malignancies, with daily dosing emerging as a strategy to minimize adverse effects.

No abstract available. Manuscript truncated after 150 words. Lymphadenopathy decreased after initiation of coccidiomycosis treatment, but symptoms and crazy paving findings continued to worsen. Further workup revealed a new diagnosis of myelodysplastic syndrome (MDS) and subsequent bronchoalveolar lavage (BAL) and histology results were consistent with secondary PAP, likely due to patient’s underlying hematologic disease. Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by the accumulation of lipoproteinaceous material in the lung alveoli. There are two types of PAP that occur in adults: Idiopathic/ autoimmune and Secondary PAP. Idiopathic/autoimmune PAP is more common and is thought to result from antibody production against granulocyte-macrophage-colony-stimulating factor (GM-CSF) that regulates surfactant homeostasis. Secondary PAP results from a precipitating condition, often inhalation exposure, underlying malignancy, or immunocompromise. The clinical manifestations of PAP are nonspecific and includes dyspnea, nonproductive cough, fatigue, and weight loss. CT may show nonspecific findings of smooth, bilateral interlobular septal thickening superimposed on a background of ground-glass opacification (crazy-paving). Diagnosis is confirmed with …

Abstract Background Clinical decision‐making for patients with myelodysplastic syndromes (MDS) is challenging, and both disease and treatment effects heavily impact health‐related quality of life (HRQoL) of these patients. Therefore, disease‐specific HRQoL measures can be critical to harness the patient voice in MDS research. Methods We report a prospective international validation study of the Quality of Life in Myelodysplasia Scale (QUALMS) with a main focus on providing information on the psychometric characteristics of its three subscales: physical burden (QUALMS‐P), emotional burden (QUALMS‐E), and benefit finding (QUALMS‐BF). The analysis is based on patients enrolled from three European countries and Israel, participating to the MDS‐RIGHT Project. The scale structure and psychometric properties of the QUALMS were assessed. Results Overall, 270 patients with a median age of 74 years were analyzed and the majority of them (60.3%) had a low MDS‐Comorbidity Index score. Results of the confirmatory factor analysis supported the underlying scale structure of the QUALMS, which, in addition to a total score, includes three subscales: QUALMS‐P, QUALMS‐E, and the QUALMS‐BF. The QUALMS‐P exhibited the highest Cronbach's alpha coefficients. Discriminant validity analysis indicated good results with the QUALMS‐P and QUALMS‐E distinguishing between patients with different performance status, comorbidity, anemia, and transfusion dependency status. No floor and ceiling effects were observed. Responsiveness to change analysis supported the validity of the measure. Patients with a hemoglobin (Hb) level of

Relapsing polychondritis is a rare systemic disease. It usually begins in middle-aged individuals. This diagnosis is mainly suggested in the presence of chondritis, i.e. inflammatory flares on the cartilage, in particular of the ears, nose or respiratory tract, and more rarely in the presence of other manifestations. The formal diagnosis of relapsing polychondritis cannot be established with certainty before the onset of chondritis, which can sometimes occur several years after the first signs. No laboratory test is specific of relapsing polychondritis, the diagnosis is usually based on clinical evidence and the elimination of differential diagnoses. Relapsing polychondritis is a long-lasting and often unpredictable disease, evolving in the form of relapses interspersed with periods of remission that can be very prolonged. Its management is not codified and depends on the nature of the patient's symptoms and association or not with myelodysplasia/vacuoles, E1 enzyme, X linked, autoinflammatory, somatic (VEXAS). Some minor forms can be treated with non-steroidal anti-inflammatory drugs, or a short course of corticosteroids with possibly a background treatment of colchicine. However, the treatment strategy is often based on the lowest possible dosage of corticosteroids combined with background treatment with conventional immunosuppressants (e.g. methotrexate, azathioprine, mycophenolate mofetil, rarely cyclophosphamide) or targeted therapies. Specific strategies are required if relapsing polychondritis is associated with myelodysplasia/VEXAS. Forms limited to the cartilage of the nose or ears have a good prognosis. Involvement of the cartilage of the respiratory tract, cardiovascular involvement, and association with myelodysplasia/VEXAS (more frequent in men over 50 years of age) are detrimental to the prognosis of the disease. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndrome includes a broad range of myeloid neoplasms characterized by cytopenia and morphologic dysplasia. Recently, 2 new classification systems emerged to further define how these diseases are diagnosed and risk stratified. This review compares these models, provides detailed approaches, and reveals practical ways to move forward in clinical practice of myelodysplastic syndrome diagnosis. [ABSTRACT FROM AUTHOR]

TP53 mutations are less frequent in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) than in solid tumors, except in secondary and therapy-related MDS/AMLs, and in cases with complex monosomal karyotype. As in solid tumors, missense mutations predominate, with the same hotspot mutated codons (particularly codons 175, 248, 273). As TP53-mutated MDS/AMLs are generally associated with complex chromosomal abnormalities, it is not always clear when TP53 mutations occur in the pathophysiological process. It is also uncertain in these MDS/AML cases, which often have inactivation of both TP53 alleles, if the missense mutation is only deleterious through the absence of a functional p53 protein, or through a potential dominant-negative effect, or finally a gain-of-function effect of mutant p53, as demonstrated in some solid tumors. Understanding when TP53 mutations occur in the disease course and how they are deleterious would help to design new treatments for those patients who generally show poor response to all therapeutic approaches. [ABSTRACT FROM AUTHOR]

Background: Clinical decision‐making for patients with myelodysplastic syndromes (MDS) is challenging, and both disease and treatment effects heavily impact health‐related quality of life (HRQoL) of these patients. Therefore, disease‐specific HRQoL measures can be critical to harness the patient voice in MDS research. Methods: We report a prospective international validation study of the Quality of Life in Myelodysplasia Scale (QUALMS) with a main focus on providing information on the psychometric characteristics of its three subscales: physical burden (QUALMS‐P), emotional burden (QUALMS‐E), and benefit finding (QUALMS‐BF). The analysis is based on patients enrolled from three European countries and Israel, participating to the MDS‐RIGHT Project. The scale structure and psychometric properties of the QUALMS were assessed. Results: Overall, 270 patients with a median age of 74 years were analyzed and the majority of them (60.3%) had a low MDS‐Comorbidity Index score. Results of the confirmatory factor analysis supported the underlying scale structure of the QUALMS, which, in addition to a total score, includes three subscales: QUALMS‐P, QUALMS‐E, and the QUALMS‐BF. The QUALMS‐P exhibited the highest Cronbach's alpha coefficients. Discriminant validity analysis indicated good results with the QUALMS‐P and QUALMS‐E distinguishing between patients with different performance status, comorbidity, anemia, and transfusion dependency status. No floor and ceiling effects were observed. Responsiveness to change analysis supported the validity of the measure. Patients with a hemoglobin (Hb) level of <11 g/dL at study entry, who subsequently showed an improvement in their Hb levels, also reported a mean score change of 9 and 8 points (scales ranging between 0 and 100) in the expected direction of the QUALMS‐E and QUALMS‐P, respectively. Conclusions: Our study provides additional validation data on the QUALMS from the international MDS‐RIGHT Project. The use of this disease‐specific HRQoL measure may contribute to raise quality standards of patient‐centered outcomes research in MDS. [ABSTRACT FROM AUTHOR]

Background: The vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a newly identified autoinflammatory disorder related to somatic UBA1 mutations. Up to 72% of patients may show lung involvement.Research Question: What are the pleuropulmonary manifestations in VEXAS syndrome?Study Design and Methods: One hundred fourteen patients were included in the French cohort of VEXAS syndrome between November 2020 and May 2021. Each patient included in the study who had an available chest CT scan was discussed in an adjudication multidisciplinary team and classified as showing potentially pleuropulmonary-specific involvement of VEXAS syndrome or others.Results: Fifty-one patients had a CT scan available for review and 45 patients (39%) showed pleuropulmonary abnormalities on chest CT scan that were considered related to VEXAS syndrome after adjudication. Most patients were men (95%) with a median age 67.0 years at the onset of symptoms. Among these 45 patients, 44% reported dyspnea and 40% reported cough. All 45 patients showed lung opacities on chest CT scan (including ground-glass opacities [87%], consolidations [49%], reticulation [38%], and septal lines [51%]) and 53% of patients showed pleural effusion. Most patients showed improvement with prednisone, but usually required > 20 mg/d. The main clinical and biological features as well the median survival did not differ between the 45 patients with pleuropulmonary involvement and the rest of the cohort, suggesting that the prevalence of pleuropulmonary involvement might have been underdiagnosed in the rest of the cohort.Interpretation: Pulmonary manifestations are frequent in VEXAS syndrome, but rarely are at the forefront. The initial outcome is favorable with prednisone and does not seem to lead to pulmonary fibrosis. [ABSTRACT FROM AUTHOR]

Ischemic myelomalacia secondary to fibrocartilaginous emboli (FCE) is an idiopathic disease in humans and animals. On the other hand, congenital spinal cord malformations result from neural tube defects in fetal development (ie, spinal dysraphism), with structural anomalies referred to collectively as myelodysplasia. Spinal dysraphisms are frequently accompanied by skin and vertebral abnormalities because of the embryogenic relationship. In this observational case study, we report the pathologic findings of 13, 18- to 24-weeks-old pigs from a large conventional operation that presented with acute paraparesis. Ischemic myelomalacia secondary to FCE was observed in 5 of 13 examined pigs. Congenital spinal cord malformations located between the caudal thoracic and sacral spinal cord were identified in 7 pigs, with structural abnormalities that ranged from diplomyelia/split cord malformation to segmental spinal dysgenesis (myelodysplasia) to caudal agenesis. Concurrent myelomalacia and congenital spinal cord malformations in the same or different sites were noted in 2 pigs. No spinal lesion was observed in 3 pigs. Although gross vertebral abnormalities were not observed herein, intervertebral instability due to minor defects in the articular facets, as well as other unidentified factors, is suspected to contribute high incidence of FCE. It is likely that these congenital malformations were previously underdiagnosed or are possibly new conditions associated with continuous inbreeding and genetic improvement in the modern swine industry. [ABSTRACT FROM AUTHOR]