Gut Microbiota Composition Correlates with Disease Severity in Myelodysplastic Syndrome.

The myelodysplastic syndrome (MDS) is a heterogeneous group of clonal disorders of hematopoietic progenitor cells related to ineffective hematopoiesis and an increased risk of transformation to acute myelogenous leukemia. MDS is divided into categories, namely lineage dysplasia (MDS-SLD), MDS with ring sideroblasts (MDS-RS), MDS with multilineage dysplasia (MDS-MLD), MDS with excess blasts (MDS-EB). The International Prognostic Classification System (IPSS) ranks the patients as very low, low, intermediate, high, and very high based on disease evolution and survival rates. Evidence points to toll-like receptor (TLR) abnormal signaling as an underlying mechanism of this disease, providing a link between MDS and immune dysfunction. Microbial signals, such as lipopolysaccharides from gram-negative bacteria, can activate or suppress TLRs. Therefore, we hypothesized that MDS patients present gut microbiota alterations associated with disease subtypes and prognosis. To test this hypothesis, we sequenced the 16S rRNA gene from fecal samples of 30 MDS patients and 16 healthy elderly controls. We observed a negative correlation between Prevotella spp. and Akkermansia spp. in MDS patients compared with the control group. High-risk patients presented a significant increase in the genus Prevotella spp. compared to the other risk categories. There was a significant reduction in the abundance of the genus Akkermansia spp. in high-risk patients compared with low- and intermediate-risk. There was a significant decrease in the genus Ruminococcus spp. in MDS-EB patients compared with controls. Our findings show a new association between gut dysbiosis and higher-risk MDS, with a predominance of gram-negative bacteria.

Myelodysplastic syndromes mortality in Spain: a comprehensive age-period-cohort and joinpoint analysis.

OBJECTIVE: The present study aims to assess the mortality trends in myelodysplastic syndromes (MDS) in Spain from 1980 to 2021. METHODS: Deaths and mid-year population data were collected from the National Institute of Statistics. We estimated age-standardised mortality rates (ASMRs) per 100,000 person-years for all ages and ages 35-64. Joinpoint regression identified significant changes in mortality trends. The independent effects of age, period and birth cohort on MDS mortality were also examined. RESULTS: MDS-related deaths gradually increased from 36 in 1980 to 1118 in 2021, with an overall increase of 6.6% in age-standardised mortality rates (ASMRs) for both men and women. Joinpoint analysis identified four periods for both men and women: 1980-1987 (stable rates), 1987-1990 (sharp increase), 1990-1999 (slower increase) and 1999-2021 (stable rates). ASMRs (35-64 years) increased by 2.5% over the study period, with a turning point identified in 1996 when rates decreased. Mortality from MDS increases with age and is higher in men. The cohort's relative risk increased until the mid-1950s and then stabilised, whilst the period relative risk increased between 1982 and 1996 and then stabilised. CONCLUSION: The results of this study indicate a progressive increase in MDS-related deaths in Spain between 1980 and 2021. Notably, this increase was more pronounced in men than in women. Analysis of birth cohort trends revealed shifts in MDS risk, characterised by an increase until the mid-twentieth century, followed by a stabilisation. Using joinpoint analysis, four distinct periods were identified, shedding light on the changing patterns of mortality over time. These findings help to shape future research directions and inform public health strategies. They also provide optimism for advances in MDS treatment and potential reductions in mortality.

[Pancytopenia associated to acute myeloid leukemia: a case report of aleukemic leukemia]. / Pancitopenia asociada a leucemia mieloide aguda: reporte de un caso de leucemia aleucémica.

Background: Acute myeloid leukemia (AML) is characterized by the presence of ≥ 20% myeloblasts in peripheral blood or bone marrow, as well as specific cytogenetic alterations. It can appear as a de novo disease or be associated with other hematologic diseases, which is why the clinical presentation is heterogeneous. Pancytopenia as a manifestation of aleukemic leukemia is a rare entity. Here, we described a case of AML that presented with pancytopenia as the only manifestation in a secondary care center. Clinical case: 72-year-old man, hospitalized due to pancytopenia, with no history of hematological diseases, asymptomatic, without hepatosplenomegaly or bleeding. Flow cytometry revealed pancytopenia without blasts in peripheral blood. Secondary causes of pancytopenia as infections, splenomegaly and nutritional deficiencies where ruled out. Bone marrow aspirate showed infiltration by 45% of myeloblasts and myelodysplasia. Immunophenotype was compatible with AML. Patient was sent to the Hematology Department at Centro Médico Nacional Siglo XXI (21st Century National Medical Center) to start chemotherapy. Conclusions: AML that is presented as pancytopenia should be considered in the evaluation of marrow failure syndrome. In the context of our hospital, morphological findings remains an essential tool for early diagnosis, since more refined studies such as immunophenotyping and cytogenetic testing are unreachable in a timely manner.

Introducción: La leucemia mieloide aguda (LMA) se caracteriza por presentar ≥ 20% de mieloblastos en sangre periférica o médula ósea, así como alteraciones citogenéticas específicas. Surge como enfermedad de novo o asociada a trastornos hematológicos, por lo que la presentación clínica es heterogénea. La presentación como pancitopenia (leucemia aleucémica) es rara. El objetivo de este trabajo es presentar un caso de LMA que cursó con pancitopenia como única manifestación clínica en un hospital de segundo nivel de atención. Caso clínico: hombre de 72 años, hospitalizado por hallazgo de pancitopenia, sin historial de enfermedades hematológicas, asintomático, sin adenomegalias ni hemorragia. La citometría hemática documentó pancitopenia sin blastos en sangre periférica. Se descartaron causas secundarias como infección, esplenomegalia y deficiencias nutricionales. En el aspirado de médula ósea se observó 45% de mieloblastos y mielodisplasia. El inmunofenotipo fue compatible con LMA. El paciente fue referido a Hematología del Centro Médico Nacional Siglo XXI para iniciar quimioterapia. Conclusiones: la LMA que se presenta como pancitopenia debe ser tomada en cuenta en el protocolo diagnóstico de síndrome de falla medular. En el contexto de nuestro hospital, la morfología hematológica sigue siendo una herramienta indispensable para el diagnóstico temprano de este tipo de enfermedades, ya que estudios más sofisticados, como el inmunofenotipo y la citogenética, no se encuentran disponibles de forma oportuna.

Hematologic malignancies of primary bone marrow involvement: a decade's experience in Bahrain

ABSTRACT Introduction: The data on the pattern of primary hematologic malignancies in Bahrain is sparse, although previously published studies suggested rising trends in their incidence. This study aimed to compare with regional and world data and identify any changing trends. Methods: A retrospective cross-sectional chart analysis study was done on all cases of primary hematologic malignancies of bone marrow origin of Bahraini nationals presenting during the 10-year period from January 2005 to December 2014 at the sole oncology referral center in Bahrain during the study period. Results: In a total of 272 cases, the primary hematologic malignancies in decreasing order of frequency with respective median ages at diagnosis were: acute myeloid leukemia (AML; 26.1%, 39 years), acute lymphoblastic leukemia (ALL; 22.8%, 9 years), multiple myeloma (MM, 16.2%, 57 years), chronic myeloid leukemia (CML, 14%, 39.5 years), myelodysplastic syndromes (MDS; 12.5%, 56 years) and chronic lymphocytic leukemia (CLL; 5.5%, 65 years). The overall crude annual incidence rate of these malignancies was 4.8/105 population. Age-specific incidence rates were found to increase dramatically with age, except for ALL, for which it peaked in the pediatric age group. The age-standardized incidence rates (ASIRs) per 105 per year were 1.47 (AML), 1.13 (MM), 0.93 (ALL), 0.85 (MDS), 0.81 (CML) and 0.44 (CLL). Conclusion: The pattern of primary hematologic malignancies in Bahrain shows unique features that distinguish it from trends reported in Eastern and Western world populations.

Hematologic malignancies of primary bone marrow involvement: a decade's experience in Bahrain.

INTRODUCTION: The data on the pattern of primary hematologic malignancies in Bahrain is sparse, although previously published studies suggested rising trends in their incidence. This study aimed to compare with regional and world data and identify any changing trends. METHODS: A retrospective cross-sectional chart analysis study was done on all cases of primary hematologic malignancies of bone marrow origin of Bahraini nationals presenting during the 10-year period from January 2005 to December 2014 at the sole oncology referral center in Bahrain during the study period. RESULTS: In a total of 272 cases, the primary hematologic malignancies in decreasing order of frequency with respective median ages at diagnosis were: acute myeloid leukemia (AML; 26.1%, 39 years), acute lymphoblastic leukemia (ALL; 22.8%, 9 years), multiple myeloma (MM, 16.2%, 57 years), chronic myeloid leukemia (CML, 14%, 39.5 years), myelodysplastic syndromes (MDS; 12.5%, 56 years) and chronic lymphocytic leukemia (CLL; 5.5%, 65 years). The overall crude annual incidence rate of these malignancies was 4.8/105 population. Age-specific incidence rates were found to increase dramatically with age, except for ALL, for which it peaked in the pediatric age group. The age-standardized incidence rates (ASIRs) per 105 per year were 1.47 (AML), 1.13 (MM), 0.93 (ALL), 0.85 (MDS), 0.81 (CML) and 0.44 (CLL). CONCLUSION: The pattern of primary hematologic malignancies in Bahrain shows unique features that distinguish it from trends reported in Eastern and Western world populations. Compared to previously published reports, ASIR trends decreased in CML and ALL but increased in MDS and MM.

Mieloma múltiple con IgM de superficie precedido por síndrome mielodisplásico en paciente anciana / Surface membrane IgM multiple myeloma preceded by myelodysplastic syndrome in an elderly patient

Introducción: El mieloma múltiple con expresión de inmunoglobulina M de superficie constituye una enfermedad rara cuya causa es desconocida y se caracteriza por una alta tasa de anormalidades genéticas en las células plasmáticas o sus precursores. Objetivo: Determinar las características clínicas y sus asociaciones con la expresión inmunofenotípica de inmunoglobulina M de superficie e inmunohistoquímica de CD20 en una paciente afectada de mieloma múltiple precedido por síndrome mielodisplásico. Presentación del caso: Paciente femenina, 68 años de edad. Admitida en el Servicio de Hematología Clínica. Al momento del diagnóstico presentó palidez, trombocitopenia, hipercalcemia y lesiones óseas. Inicialmente, mediante citometría de flujo se detectaron patrones aberrantes para granulocitos, neutrófilos, monocitos y serie eritroide, sugerentes de síndrome mielodisplásico. Posteriormente se observó aumento de las células plasmáticas del 18 % en el frotis de médula ósea, exhibiendo una morfología similar a linfocitos. Se reportó una población patológica de 6 % de la celularidad total, mostrando positividad para CD38, CD117 e inmunoglobulina M de superficie, negatividad para CD19 y CD45, fenotipo coherente con células plasmáticas anormales. Adicionalmente resultados de inmunohistoquímica relataron tinción difusa de CD20 en biopsia de médula ósea. La paciente logró recuperarse luego de un trasplante autólogo de células progenitoras hematopoyéticas. Conclusión: Los resultados resaltan la importancia de diagnosticar y monitorear casos únicos que permitan un tratamiento oportuno del paciente.

Introduction: Multiple Myeloma with expression of surface immunoglobulin M is a rare entity, whose cause is unknown, and is characterized by a high rate of genetic abnormalities in plasma cells or their precursors. Objective: To determining the clinical characteristics and their associations with the immunophenotypic expression of surface immunoglobulin M and CD20 immunohistochemistry in a patient affected by Multiple Myeloma preceded by Myelodysplastic syndrome. Case presentation: A 68-year-old female patient is admitted to the Clinical Hematology Service. At the time of diagnosis, she presented pallor, thrombocytopenia, hypercalcemia, and bone lesions. Initially, flow cytometry detected aberrant patterns for neutrophilic granulocytes, monocytes, and the erythroid series suggestive of myelodysplastic syndrome. Subsequently, an 18% increase in plasma cells was observed in the bone marrow smear, exhibiting a lymphocyte-like morphology. A pathological population of 6% of the total cellularity was reported, showing positivity for CD38, CD117 and surface immunoglobulin M, negativity for CD19 and CD45, a phenotype consistent with abnormal plasma cells. Additionally, immunohistochemical results reported diffuse CD20 staining in bone marrow biopsy. The patient managed to recover after an autologous hematopoietic stem cell transplant. Conclusion: The results found highlight the importance of diagnosing and monitoring single cases that allow timely treatment of the patient.

Co-occurrence of myeloid neoplasm and plasma cell neoplasm.

Co-occurrence of myelodysplastic syndrome (MDS) and plasma cell neoplasm in patients with no history of chemo and/or radiotherapy is rarely reported. Herein, we report a case of a female in her seventieth decade of life who was referred to the hospital for pancytopenia. The patient was asymptomatic and was doing well overall. Serum protein electrophoresis was remarkable for a lambda-restricted monoclonal protein (IgG) estimated at 1.8g/dL. Immunoglobulin G serum level was also elevated, and serum Kappa/Lambda free light chain ratio was decreased. At that time, a bone marrow biopsy showed myelodysplastic syndrome with excess blasts-2 (MDS-EB2) and a monoclonal plasma cell proliferation. Some studies have shown that patients with plasma cell neoplasm could be associated with an increased risk of developing MDS compared to the general population. Based on reviewing the literature, to our knowledge, the pathological mechanism of the co-occurrence of both diseases is not yet clear.

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome (VEXAS syndrome) with prominent supraglottic larynx involvement: a case-based review.

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome (VEXAS syndrome) is a recently described genetic disorder that gathers autoinflammatory symptoms and myeloid dysplasia. The first description was reported in 2020, and subsequently, a growing number of cases have been described worldwide. Herein, we describe a case of a 72-year-old male patient with VEXAS syndrome with p.Met41Val mutation of the UBA1 gene, prominent supraglottic larynx involvement, and costochondritis. To our knowledge, this is the first report of VEXAS syndrome in Colombia and South America. This disease could present features of relapsing polychondritis, polyarteritis nodosa, giant cell arteritis, and Sweet syndrome, associated with hematologic involvement, including cytopenias, myelodysplastic syndrome, or thromboembolic disease. Supraglottic larynx chondritis and costochondritis are atypical manifestations. These features were proposed previously to differentiate relapsing polychondritis from VEXAS syndrome but are not entirely reliable like in the case described. A diagnosis of VEXAS should be considered in male patients with incomplete or complete features of the previously described conditions, refractory to treatment, requiring high-dose glucocorticoids, and associated progressive hematologic abnormalities. Key Points • VEXAS syndrome is a recently described genetic (somatic mutations in UBA1 gene) disorder that gathers autoinflammatory and hematologic manifestations. • VEXAS syndrome should be considered in male patients with incomplete or complete features of relapsing polychondritis, polyarteritis nodosa, giant cell arteritis, and Sweet syndrome, refractory to treatment, associated with hematologic involvement, including cytopenias, myelodysplastic syndrome, or thromboembolic disease. • Glucocorticoids ameliorate symptoms effectively. However, other treatment options are limited due to a lack of evidence. Traditional immunosuppressants and biological therapy have been used empirically with limited efficacy and a transient effect. Bone marrow transplant offers a curative approach, but it has high morbidity and mortality.

HLA-DRB1 and cytokine polymorphisms in Brazilian patients with myelodysplastic syndromes and its association with red blood cell alloimmunization.

OBJECTIVE(S): This study aimed investigate association of HLA-DRB1 and cytokine polymorphisms with red blood cell(RBC) alloimmunization in Brazilian Myelodysplastic syndrome(MDS) patients with prior exposure to RBC transfusion. BACKGROUND: MDS patients are at risk RBC alloimmunization due to chronic RBC transfusion. However, differences in immune response of MDS transfused patients are not completely known. METHODS/MATERIALS: A retrospective cohort of 87 polytransfused patients with MDS including 28 alloimmunized (PA) and 59 non-alloimmunized (PNA) was evaluated in three Brazilian reference hospitals. HLA-DRB1genotype was performed by polymerase chain reaction (PCR)-SSOP (Luminex platform) and cytokine polymorphisms analysed by PCR and TaqMan assays. RESULTS: While HLA-DRB1 allele frequencies did not differ between groups, IL17A 197G > A SNP and IL4 polymorphisms showed significant correlation with RBC alloimmunization. IL17A 197A allele A and AA genotype were significantly more frequent in PA than PNA(A, 46.4% versus 27.1%, p = 0.012; OR = 2.3; 95%CI = 1.1-4.9; AA, 25% versus 6.8%, p = 0.041; OR = 6.2; 95%CI 1.3-30.8). Moreover, significant association of alloimmunization to Rh antigens with IL17A 197A allele and AA genotype was also identified in PA group(A, 45% versus 27.1%, p = 0.036; OR = 2.5; 95% CI 1.1-5.7; AA, 30% versus 6.8%, p = 0.042; OR = 7.9; 95%CI 1.5-42.3). Genotype A1A2 of IL4 intron 3 was overrepresented in PA(50% versus 16.9%, p = 0.009; OR = 4.97; 95%CI 1.6-15.5). Similarly, IL4-590 CT genotype was overrepresented in PA(53.6% versus 28.8%, p = 0.049; OR = 3.3; 95%CI 1.2-9.3). CONCLUSIONS: This study showed no association regarding HLA-DRB1 alleles for RBC alloimmunization risk or protection, however the IL17A 197G>A, IL4 intron 3 and IL4 590C>T SNP was significantly associated to RBC alloimmunization risk in this cohort of Brazilian MDS patients.

Pulmonary Alveolar Proteinosis due to Familial Myelodysplastic Syndrome with resolution after stem cell transplant.

Pulmonary alveolar proteinosis (PAP) is a rare lung disease with an incidence of 0.2 cases per million. PAP has multiple causes, including autoimmune, hereditary, congenital, or secondary. The latter includes hematologic conditions and exposure to different kinds of dust. Most patients present fever, dyspnea, and cough. The chest computed tomography (CT) may reveal the crazy-paving polygonal shapes with superimposed ground glass opacities delimited by thickened interlobular septa; however, this finding is more prevalent in patients with autoimmune PAP. Bronchoalveolar lavage (BAL) shows a milky-opaque appearance with PAS-positive debris on cytology. Treatment is focused on the underlying disease; however, some patients may require whole lung lavage for symptomatic management. We report a case of a 30-year-old female with a history of familial myelodysplastic syndrome (MDS) with GATA 2 mutation who presented to the outpatient clinic with several months of progressive dyspnea and nonproductive cough. The chest CT revealed bilateral ground-glass opacities prominently in the upper lobes. She underwent a bronchoscopy with lavage and biopsy, which revealed fragments of lung parenchyma with intra-alveolar coarse granular eosinophilic material strongly positive for PAS and d-PAS. The overall clinical presentation and histologic findings were diagnostic of PAP. Her GM-CSF was negative, and due to her history of MDS, secondary PAP (S-PAP) was strongly suspected. She underwent a successful allogeneic bone marrow pluripotent stem cell transplant to treat the myelodysplastic syndrome, with a follow-up chest CT showing clear lung parenchyma. The patient had resolution of symptoms about four months after the bone marrow transplant, confirming the diagnosis of S-PAP.

Consensus Statement: Importance of Timely Access to Multiple Myeloma Diagnosis and Treatment in Central America and the Caribbean.

Background: In Central America and the Caribbean, multiple myeloma (MM) patients face significant barriers to diagnosis and treatment. The aim of this study is to describe the current situation of MM in the region, discuss the current barriers to timely diagnosis and proper treatment, and develop consensus recommendations to address these issues. Methods: Nine experts from five countries took part in a virtual consensus meeting on MM in Central America and the Caribbean. During the meeting, experts analyzed the disease burden, the current conditions for disease management, and access to treatment in the region. The participants reached a consensus on the extent of the problem and the necessary measures. Results: Hard evidence on the incidence and prevalence of MM in the region is scarce, but the experts perceive an increase in MM cases. The lack of data on the direct and indirect costs at the local and regional levels obscures the impact of the disease and limits awareness among decision-makers. Most patients are diagnosed late and face long waiting times and geographical barriers to access treatment. Access to efficacious innovative therapies that increase survival time is limited due to access barriers within health systems. Conclusions: There was consensus on five recommendations: 1) to generate evidence; 2) to educate the public; 3) to increase timely diagnosis and facilitate access to treatment; 4) to promote interaction, collaboration, and participation among all sectors involved in the decision-making process; and 5) to guarantee timely access to new therapies.

Tissue methylation and demethylation influence translesion synthesis DNA polymerases (TLS) contributing to the genesis of chromosomal abnormalities in myelodysplastic syndrome.

AIMS: DNA methylation has its distribution influenced by DNA demethylation processes with the catalytic conversion of 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). Myelodysplastic syndrome (MDS) has been associated with epigenetic dysregulation of genes related to DNA repair system, chronic immune response and cell cycle. METHODS: We evaluated the tissue DNA methylation/hydroxymethylation in bone marrow trephine biopsies of 73 patients with MDS, trying to correlate with the mRNA expression of 21 genes (POLH, POLL, REV3L, POLN, POLQ, POLI, POLK, IRF-1, IRF-2, IRF-3, IRF-4, IRF-5, IRF6, IRF-7, IRF-8,IRF-9, MAD2, CDC20, AURKA, AURKB and TPX2). RESULTS: The M-score (5mC) was significantly higher in patients with chromosomal abnormalities than patients with normal karyotype (95% CI -27.127779 to -2.368020; p=0.022). We observed a higher 5mC/5hmC ratio in patients classified as high-risk subtypes compared with low-risk subtypes (95% CI -72.922115 to -1.855662; p=0.040) as well as patients with hypercellular bone marrow compared with patients with normocellular/hypocellular bone marrow (95% CI -69.189259 to -0.511828; p=0.047) and with the presence of dyserythropoiesis (95% CI 17.077703 to 51.331388; p=0.001). DNA pols with translesion activity are significantly influenced by methylation. As 5mC immunoexpression increases, the expressions of POLH (r=-0.816; r2 =0.665; p=0.000), POLQ (r=-0.790; r2=0.624; p=0.001), PCNA (r=-0.635; r2=0.403; p=0.020), POLK (r=-0.633; r2=0.400; p=0.036 and REV1 (r=-0.578; r2=0.334; p=0.049) decrease. CONCLUSIONS: Our results confirm that there is an imbalance in the DNA methylation in MDS, influencing the development of chromosomal abnormalities which may be associated with the low expression of DNA polymerases with translesion synthesis polymerases activity.

Pulmonary Alveolar Proteinosis due to Familial Myelodysplastic Syndrome with resolution after stem cell transplant

ABSTRACT Pulmonary alveolar proteinosis (PAP) is a rare lung disease with an incidence of 0.2 cases per million. PAP has multiple causes, including autoimmune, hereditary, congenital, or secondary. The latter includes hematologic conditions and exposure to different kinds of dust. Most patients present fever, dyspnea, and cough. The chest computed tomography (CT) may reveal the crazy-paving polygonal shapes with superimposed ground glass opacities delimited by thickened interlobular septa; however, this finding is more prevalent in patients with autoimmune PAP. Bronchoalveolar lavage (BAL) shows a milky-opaque appearance with PAS-positive debris on cytology. Treatment is focused on the underlying disease; however, some patients may require whole lung lavage for symptomatic management. We report a case of a 30-year-old female with a history of familial myelodysplastic syndrome (MDS) with GATA 2 mutation who presented to the outpatient clinic with several months of progressive dyspnea and nonproductive cough. The chest CT revealed bilateral ground-glass opacities prominently in the upper lobes. She underwent a bronchoscopy with lavage and biopsy, which revealed fragments of lung parenchyma with intra-alveolar coarse granular eosinophilic material strongly positive for PAS and d-PAS. The overall clinical presentation and histologic findings were diagnostic of PAP. Her GM-CSF was negative, and due to her history of MDS, secondary PAP (S-PAP) was strongly suspected. She underwent a successful allogeneic bone marrow pluripotent stem cell transplant to treat the myelodysplastic syndrome, with a follow-up chest CT showing clear lung parenchyma. The patient had resolution of symptoms about four months after the bone marrow transplant, confirming the diagnosis of S-PAP.

Co-occurrence of myeloid neoplasm and plasma cell neoplasm

ABSTRACT Co-occurrence of myelodysplastic syndrome (MDS) and plasma cell neoplasm in patients with no history of chemo and/or radiotherapy is rarely reported. Herein, we report a case of a female in her seventieth decade of life who was referred to the hospital for pancytopenia. The patient was asymptomatic and was doing well overall. Serum protein electrophoresis was remarkable for a lambda-restricted monoclonal protein (IgG) estimated at 1.8g/dL. Immunoglobulin G serum level was also elevated, and serum Kappa/Lambda free light chain ratio was decreased. At that time, a bone marrow biopsy showed myelodysplastic syndrome with excess blasts-2 (MDS-EB2) and a monoclonal plasma cell proliferation. Some studies have shown that patients with plasma cell neoplasm could be associated with an increased risk of developing MDS compared to the general population. Based on reviewing the literature, to our knowledge, the pathological mechanism of the co-occurrence of both diseases is not yet clear.

Arhgap21 Deficiency Results in Increase of Osteoblastic Lineage Cells in the Murine Bone Marrow Microenvironment.

ARHGAP21 is a member of the RhoGAP family of proteins involved in cell growth, differentiation, and adhesion. We have previously shown that the heterozygous Arhgap21 knockout mouse model (Arhgap21+/-) presents several alterations in the hematopoietic compartment, including increased frequency of hematopoietic stem and progenitor cells (HSPC) with impaired adhesion in vitro, increased mobilization to peripheral blood, and decreased engraftment after bone marrow transplantation. Although these HSPC functions strongly depend on their interactions with the components of the bone marrow (BM) niche, the role of ARHGAP21 in the marrow microenvironment has not yet been explored. In this study, we investigated the composition and function of the BM microenvironment in Arhgap21+/- mice. The BM of Arhgap21+/- mice presented a significant increase in the frequency of phenotypic osteoblastic lineage cells, with no differences in the frequencies of multipotent stromal cells or endothelial cells when compared to the BM of wild type mice. Arhgap21+/- BM cells had increased capacity of generating osteogenic colony-forming units (CFU-OB) in vitro and higher levels of osteocalcin were detected in the Arhgap21+/- BM supernatant. Increased expression of Col1a1, Ocn and decreased expression of Trap1 were observed after osteogenic differentiation of Arhgap21+/- BM cells. In addition, Arhgap21+/- mice recipients of normal BM cells showed decreased leucocyte numbers during transplantation recovery. Our data suggest participation of ARHGAP21 in the balanced composition of the BM microenvironment through the regulation of osteogenic differentiation.

Myeloid sarcoma: an uncommon presentation of myeloid neoplasms; a case series of 4 rare cases reported in a tertiary care institute.

Myeloid sarcoma (MS) is a rare extramedullary neoplasm of myeloid cells, which can arise before, concurrently with, or following hematolymphoid malignancies. We report 04 such cases of MS, diagnosed in this institute over a period of 6 years, during various phases of their respective myeloid neoplasms/leukemias. These cases include MS occurring as a relapse of AML (Case 1), MS occurring as an initial presentation of CML (Case 2), MS occurring during ongoing chemotherapy in APML (Case 3), and MS presenting as a progression of MDS to AML (Case 4). In the absence of relevant clinical history and unemployment of appropriate immunohistochemical (IHC) studies, these cases have a high risk of being frequently misdiagnosed either as Non-Hodgkin's Lymphoma (NHL) or small round cell tumors or undifferentiated carcinomas, which may further delay their management, making an already bad prognosis worse. This case series has been designed to throw light on the varied presentation of MS and the lineage differentiation of its neoplastic cells through the application of relevant IHC markers along with their clinical correlation.

Myelodysplastic syndrome in a 30-year-old man with coronavirus disease 2019 (COVID-19): a diagnostic challenge.

BACKGROUND: Myelodysplastic syndromes (MDS) mainly occur in the elderly but can rarely affect younger individuals too. The correct diagnosis relies on careful morphologic evaluation, cytogenetic/molecular results, and excluding reactive conditions mimicking MDS. We present the clinical, pathologic, cytogenetic, and molecular features of a case of MDS with excess blasts-2 (MDS-EB-2) in a 30-year-old male who was found to have pancytopenia during his hospitalization for coronavirus disease 2019 (COVID-19) and discuss the diagnostic challenges of MDS in patients with COVID-19. CASE PRESENTATION: A 30-year-old man presented to an outside hospital with fever, chills, weakness, coughing spells, dizziness and shortness of breath and was diagnosed with bilateral pneumonia due to COVID-19. At the outside hospital, he was found to be pancytopenic, and a subsequent bone marrow aspiration and biopsy raised concern for a COVID-19 induced hemophagocytic lymphohistiocytosis. In addition, MDS could not be ruled out. The patient was thus referred to our institute for further management. The patient's peripheral blood showed pancytopenia with occasional dysplastic neutrophils and a few teardrop cells. Given the diagnostic uncertainty, a bone marrow aspiration and a biopsy were repeated revealing a hypercellular bone marrow with erythroid hyperplasia, megakaryocytic hyperplasia, trilineage dysplasia, increased blasts (13%), many ring sideroblasts, and mild to moderate myelofibrosis, consistent with MDS-EB-2. Chromosomal analysis revealed isochromosome 14. Next generation sequencing demonstrated SF3B1 K700E mutation. DISCUSSION AND CONCLUSION: The diagnosis of MDS can be challenging, particularly in young patients. Cytopenia and myelodysplastic features have been reported in COVID-19 patients, making the diagnosis of MDS more elusive. A careful pathologic examination of the bone marrow with ancillary studies including flow cytometry, immunohistochemistry, and cytogenetic and molecular studies in combination with a thorough clinical evaluation, leads to the accurate diagnosis.

Association between red blood cell transfusion dependence and burden in patients with myelodysplastic syndromes: A systematic literature review and meta-analysis.

Myelodysplastic syndromes (MDS) are a group of malignant hematologic diseases characterized by ineffective hematopoiesis, which may lead to chronic anemia and transfusion dependency, with up to 30% of patients progressing to acute myeloid leukemia (AML). Studies suggest transfusion dependency may impact overall survival (OS); however, there is a lack of evidence concerning the association between transfusion status (TS) and OS in patients with MDS who become transfusion independent (TI) after treatment. In addition, the holistic impact of TS on other clinical, economic, and humanistic outcomes has not been well understood. We conducted a systematic literature review (SLR) to understand this impact. Ten studies were included and showed consistent decrease in OS in transfusion dependent (TD) compared with TI patients. These findings were confirmed by a meta-analysis (MA) reporting better OS prognosis for TI patients. A second SLR was conducted to understand the association between TS and other clinical, economic, and humanistic outcomes. Twenty-eight studies were included and showed better prognosis for other outcomes, including AML progression and leukemia-free survival for TI patients. Risk of AML progression and cumulative non-leukemic death assessed by the MA showed a trend toward worse prognosis and higher risk of AML progression for TD patients. Lower healthcare resource utilization, better quality of life, and reduced non-leukemic death for TI patients were observed. Studies not eligible for MA also showed better clinical, economic, and humanistic outcomes for TI patients. These findings contribute to understanding the association between transfusion dependence and OS among other outcomes in patients with MDS.

5-Azacytidine restores interleukin 6-increased production in mesenchymal stromal cells from myelodysplastic patients

Introduction: Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematological diseases. In addition to defects in hematologic progenitor and stem cells, dysfunctions in the bone marrow microenvironment (BMM) participate in the MDS pathogenesis. Furthermore, the immune response is deregulated by the pro-inflammatory response prevailing in low-risk MDS, while immunosuppression predominates in high-risk MDS. Mesenchymal stromal cells (MSC), part of the BMM, are characterized by plastic adherent growth and multipotentiality. They exhibit immunomodulatory properties and sustain hematopoiesis. There is conflicting evidence regarding their status in MDS. The aim of this study was to characterize MDS-MSC and evaluate the effect of 5-Azacytidine. Methods: The MSC from MDS patients and controls were cultured and characterized according to the International Society of Cell Therapy recommendations. Immunomodulatory properties were assessed by studying the MSD cytokine production, using the cytometric bead array. We evaluated the effect of 5-Azacytidine on the MSC cytokine production. Results: We included 35 MDS patients and 22 controls. The MSC from patients and controls were cultured and characterized. The MSC from patients showed morphological differences, but there were no differences in immunophenotype or multipotentiality. The interleukin 6 (IL-6) was the main MSC secreted cytokine. The MDS-MSC produced higher levels of IL-6, IL-17, interferon gamma, or interferon γ (INF-γ), and tumor necrosis factor alpha (TNF-α). The in vitro 5-Azacytidine treatment induced a significant decrease in the IL-6 production by MDS-MSC. Conclusions: The MDS-MSC show an increased production of pro-inflammatory cytokines. The in vitro treatment with 5-Azacytidine lead to a significant reduction in the IL-6 production by the MDS-MSC, restoring the IL-6 levels to those found in controls. The MSC produced inflammatory cytokines involved in the MDS pathogenesis, representing a potential future therapeutic target. Moreover, 5-Azacytidine may have a stromal effect, modulating the immune response in MDS.

Immune Dysregulation and Recurring Mutations in Myelodysplastic Syndromes Pathogenesis.

Myelodysplastic syndromes (MDS) are clonal stem cell malignancies characterized by ineffective hematopoiesis leading to peripheral cytopenias and variable risk of progression to acute myeloid leukemia. Inflammation is associated with MDS pathogenesis. Several cytokines, reactive species of oxygen/nitrogen and growth factors are directly or indirectly involved in dysfunction of the MDS bone marrow (BM) microenvironment. Mutations in genes mainly regulating RNA splicing, DNA methylation and chromatin accessibility, transcription factors, signal transduction and the response to DNA damage contribute to ineffective hematopoiesis, genomic instability and MDS development. The inflammation-associated DNA damage in hematopoietic stem cells may also contribute to MDS development and progression with aggressive clinical characteristics. Many studies have aimed at clarifying mechanisms involved in the activity of immature myeloid cells as powerful modulators of the immune response and their correlation with aging, autoimmunity, and development of cancer. In this review, we explore recent advances and accumulating evidence uniting immune dysregulation, inflammaging and recurring mutations in the pathogenesis of MDS.