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Simple Summary: Juvenile Myelomonocytic Leukemia (JMML) is a rare and clonal hematopoietic disorder of infancy and early childhood with myeloproliferative/myelodysplastic features resulting from germline or somatic mutations in the RAS pathway. Given its rarity, management is not standardized and varies widely, ranging from observation to bone marrow transplant depending on genomic and clinical features. We describe the course of JMML or Noonan Syndrome-associated Myeloproliferative Disorder in 22 pediatric patients treated at three institutions to provide guidance for monitoring versus intervention, including transplant, supported by patient outcomes. We provide additional insight into the expected time to spontaneous resolution in those with germline PTPN11 mutations and treatment approaches for patients with germline CBL mutations where no standard exists. Juvenile Myelomonocytic Leukemia (JMML) is a rare and clonal hematopoietic disorder of infancy and early childhood with myeloproliferative/myelodysplastic features resulting from germline or somatic mutations in the RAS pathway. Treatment is not uniform, with management varying from observation to stem cell transplant. The aim of our retrospective review is to describe the treatment and outcomes of a cohort of patients with JMML or Noonan Syndrome-associated Myeloproliferative Disorder (NS-MPD) to provide management guidance for this rare and heterogeneous disease. We report on 22 patients with JMML or NS-MPD managed at three institutions in the Texas Medical Center. Of patients with known genetic mutations and cytogenetics, 6 harbored germline mutations, 12 had somatic mutations, and 9 showed cytogenetic abnormalities. Overall, 14/22 patients are alive. Spontaneous clinical remission occurred in one patient with somatic NRAS mutation, as well as two with germline PTPN11 mutations with NS-MPD, and two others with germline PTPN11 mutations and NS-MPD remain under surveillance. Patients with NS-MPD were excluded from treatment analysis as none required chemotherapeutic intervention. All patients (5/5) treated with 5-azacitidine alone and one of the four treated with 6-mercaptopurine monotherapy had a reduction in mutant variant allele frequency. Transformation to acute myeloid leukemia was seen in two patients who both died. Among patients who received transplants, 7/13 are alive, and relapse post-transplant occurred in 3/13 with a median time to relapse of 3.55 months. This report provides insight into therapy responses and long-term outcomes across different genetic subsets of JMML and lends insight into the expected time to spontaneous resolution in patients with NS-MPD with germline PTPN11 mutations. [ABSTRACT FROM AUTHOR]

Background and Aims: Peroxidase deficiency is one of the commonly inherited phagocytic defects. It has been also found to exist as a transient phenomenon in association with some clinical conditions. But that it can interfere and cause erroneous automated differential WBC count is something which is not commonly known. Materials and methods: Complete blood counts were analysed using Advia 2120i and Coulter DXH 900 haematology analysers and manually reviewed on peripheral blood smear stained with Leishman stain. Results: Peroxidase deficiency in neutrophils and eosinophils resulted in them getting counted as monocytes by the analyser causing pseudomonocytosis, pseudoneutropenia and pseudoeosinopenia. These were detected by a slide review and by reanalysing the samples on an analyser which worked on a different principle. Conclusion: There is a need to confirm monocytosis given by analysers working on the peroxidase principle with an alternate method. This will prevent needless medical investigations for pseudoneutropenia, pseudoeosinopenia and persistent monocytosis, thus preventing unwarranted mental agony and financial burden to patients. It also helps to save the laboratory's reputation. A careful review of instrument flags not only helps reach an accurate result but sometimes they can also aid in the diagnosis of a rare potential genetic disorder like MPO deficiency. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic, caused by SARS-CoV-2, has posed significant health challenges worldwide. While children generally experience less severe illness compared to adults, pneumonia remains a substantial risk, particularly for those under five years old. This study examines the clinical characteristics and treatment outcomes of pediatric COVID-19 pneumonia patients treated with favipiravir in Thailand, aiming to identify associated factors for pneumonia. A retrospective review was performed on pediatric patients aged 1 month to 18 years hospitalized with COVID-19 at Srinagarind Hospital, Khon Kaen University, from 13 January 2020 to 15 November 2021. Data on demographics, clinical symptoms, treatment, and outcomes were collected, and logistic regression analysis was used to identify factors associated with pneumonia. Among 349 hospitalized children, the median age was 8 years, with 51.9% being male. Symptoms included a fever (100%), a cough (74.2%), and a rash (24.9%). COVID-19 pneumonia was diagnosed in 54.7% of the children. Favipiravir was administered as the standard treatment, showing mild adverse effects, including a rash (4.3%) and nausea (2.8%). Monocytosis was significantly associated with COVID-19 pneumonia (aOR 30.85, 95% CI: 9.03–105.41, p < 0.001), with an ROC curve area of 0.77 (95% CI: 0.71–0.83). Pediatric COVID-19 patients typically exhibit mild-to-moderate symptoms, with pneumonia being common in the early pandemic phase. Monocytosis is a significant factor associated with COVID-19 pneumonia. Favipiravir demonstrated mild adverse effects. Further studies are needed to validate these findings across different settings and phases of the pandemic. [ABSTRACT FROM AUTHOR]

Remote limb conditioning (RLC), performed by intermittent interruption of blood flow to a limb, triggers endogenous tolerance mechanisms and improves stroke outcomes. The underlying mechanism for the protective effect involves a shift of circulating monocytes to a Ly6CHigh proinflammatory subset in normal metabolic conditions. The current study investigates the effect of RLC on stroke outcomes in subjects with obesity, a vascular comorbidity. Compared to lean mice, obese stroke mice displayed significantly higher circulating monocytes (monocytosis), increased CD45High monocytes/macrophages infiltration to the injured brain, worse acute outcomes, and delayed recovery. Unlike lean mice, obese mice with RLC at 2 hours post-stroke failed to shift circulating monocytes to pro-inflammatory status and nullified RLC-induced functional benefit. The absence of the monocyte shift was also observed in splenocytes incubated with RLC serum from obese mice, while the shift was observed in the cultures with RLC serum from lean mice. These results showed that the alteration of monocytosis and subsets underlies negating RLC benefits in obese mice and suggest careful considerations of comorbidities at the time of RLC application for stroke therapy. [ABSTRACT FROM AUTHOR]

Pregnancy is characterized by important variations in virtually every organ system to accommodate the growing and developing fetoplacental entity. Hence, the objective of this study is to assess the effect of pregnancy on hematological profile of female subjects attending a private hospital in Benin City, Edo State, Nigeria using eighty female volunteered individuals comprising sixty pregnant subjects and twenty nonpregnant subjects. The pregnant group was further categorized into three trimesters, each consisting of twenty participants. Results were presented as Mean ± SD and analyzed using GraphPad Prism 5 software (GraphPad Software Inc.), and p < 0.05 was considered statistically significant. Overall, the mean values of lymphocytes, red blood cells, hematocrit, hemoglobin, and platelets were decreased in the pregnant cohort when compared to the nonpregnant cohort, whereas an incremental rise in white blood cell, and granulocytes were observed in the pregnant cohort when compared to the nonpregnant cohort. A statistically significant difference (p < 0.05) in the mean hematocrit and hemoglobin values was observed when comparing the first-trimester participants with the control participants, although white blood cells, granulocytes, lymphocytes, red blood cells, and platelets were not different (p > 0.05). The average values for white blood cells, granulocytes, red blood cells, hematocrit, and hemoglobin between secondtrimester individuals and those of nonpregnant individuals exhibited a significant variance (p < 0.05), while the average lymphocyte and platelet counts showed no significance (p > 0.05). the mean white blood cells, granulocytes, lymphocytes, red blood cells, hematocrit, hemoglobin, and platelet counts for the third-trimester subjects were significantly different (p < 0.05) when compared to the control subjects. The study outcome suggests that pregnancy affects hematological indices and may be a risk predictor for pregnancy-associated complications. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the prevalence of hematologic findings and the relationship between hemogram parameters and brucellosis stages in patients. Methods: This multi-center study included patients older than 16 years of age who were followed up with a diagnosis of brucellosis. Patients' results, including white blood cell, hemoglobin, neutrophil, lymphocyte, monocyte, mean platelet volume, platelet and eosinophil counts were analyzed at the initial diagnosis. Results: In this study 51.3% of the patients diagnosed with brucellosis were male. The age median was 45 years for female and 41 years for male. A total of 55.1% of the patients had acute brucellosis, 28.2% had subacute, 7.4% had chronic and 9% had relapse. The most common hematologic findings in brucellosis patients were anemia (25.9%), monocytosis (15.9%), eosinopenia (10.3%), and leukocytosis (7.1%). Pancytopenia occurred in 0.8% of patients and was more prominent in the acute phase. The acute brucellosis group had lower white blood cell, hemoglobin, neutrophil, eosinophil, and platelet counts and mean platelet volume, and higher monocyte counts compared to subacute and chronic subgroups. Conclusion: It was noteworthy that in addition to anemia and monocytosis, eosinopenia was third most prominent laboratory findings in the study. Pancytopenia and thrombocytopenia rates were low. [ABSTRACT FROM AUTHOR]

Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasia that lacks effective targeted chemotherapies. Clinically, JMML manifests as monocytic leukocytosis, splenomegaly with consequential thrombocytopenia. Most commonly, patients have gain-of-function (GOF) oncogenic mutations in PTPN11 (SHP2), leading to Erk and Akt hyperactivation. Mechanism(s) involved in co-regulation of Erk and Akt in the context of GOF SHP2 are poorly understood. Here, we show that Bruton's tyrosine kinase (BTK) is hyperphosphorylated in GOF Shp2-bearing cells and utilizes B cell adaptor for PI3K to cooperate with p110δ, the catalytic subunit of PI3K. Dual inhibition of BTK and p110δ reduces the activation of both Erk and Akt. In vivo, individual targeting of BTK or p110δ in a mouse model of human JMML equally reduces monocytosis and splenomegaly; however, the combined treatment results in a more robust inhibition and uniquely rescues anemia and thrombocytopenia. RNA-seq analysis of drug-treated mice showed a profound reduction in the expression of genes associated with leukemic cell migration and inflammation, leading to correction in the infiltration of leukemic cells in the lung, liver, and spleen. Remarkably, in a patient derived xenograft model of JMML, leukemia-initiating stem and progenitor cells were potently inhibited in response to the dual drug treatment.

Background: Juvenile myelomonocytic leukemia (JMML), previously known as juvenile chronic myeloid leukaemia, is a rare, unique, and aggressive myeloproliferative neoplasm of early childhood. Making a diagnosis of JMML is challenging because of the overlapping clinical and haematological features with other myeloproliferative neoplasms (MPN). However, some unique features like monocytosis, the absence of BCR-ABL translocation, and the presence of specific mutations (PTPN-11, K-RAS, N-RAS, CBL, or NF1) clinch the correct diagnosis. Methods: A prospective analysis of six JMML patients with variable clinical features treated with injection azacytidine as frontline therapy during the study period of 2 years. Results: The median age was 4.5 years with male:female ratio 2:4. Pallor and splenomegaly were the most common presenting signs. Four patients (66.67%) achieved complete remission (CR), two patients (33.33%) had partial remission (PR), and one patient (16.67%) had progressive disease (PD). The overall survival rate was 66.67% (four out of six), and the mortality rate was 33.33%. Conclusion: Azacitidine is an effective treatment option as upfront therapy for JMML, especially in resource poor developing countries. [ABSTRACT FROM AUTHOR]

Pregnancy is characterized by important variations in virtually every organ system to accommodate the growing and developing fetoplacental entity. Hence, the objective of this study is to assess the effect of pregnancy on hematological profile of female subjects attending a private hospital in Benin City, Edo State, Nigeria using eighty female volunteered individuals comprising sixty pregnant subjects and twenty nonpregnant subjects. The pregnant group was further categorized into three trimesters, each consisting of twenty participants. Results were presented as Mean ± SD and analyzed using GraphPad Prism 5 software (GraphPad Software Inc.), and p < 0.05 was considered statistically significant. Overall, the mean values of lymphocytes, red blood cells, hematocrit, hemoglobin, and platelets were decreased in the pregnant cohort when compared to the nonpregnant cohort, whereas an incremental rise in white blood cell, and granulocytes were observed in the pregnant cohort when compared to the nonpregnant cohort. A statistically significant difference (p < 0.05) in the mean hematocrit and hemoglobin values was observed when comparing the first-trimester participants with the control participants, although white blood cells, granulocytes, lymphocytes, red blood cells, and platelets were not different (p > 0.05). The average values for white blood cells, granulocytes, red blood cells, hematocrit, and hemoglobin between second-trimester individuals and those of nonpregnant individuals exhibited a significant variance (p < 0.05), while the average lymphocyte and platelet counts showed no significance (p > 0.05). the mean white blood cells, granulocytes, lymphocytes, red blood cells, hematocrit, hemoglobin, and platelet counts for the third-trimester subjects were significantly different (p < 0.05) when compared to the control subjects. The study outcome suggests that pregnancy affects hematological indices and may be a risk predictor for pregnancy-associated complications.

Aims/hypothesisHypothalamic inflammation and sympathetic nervous system hyperactivity are hallmark features of the metabolic syndrome and type 2 diabetes. Hypothalamic inflammation may aggravate metabolic and immunological pathologies due to extensive sympathetic activation of peripheral tissues. Loss of somatostatinergic (SST) neurons may contribute to enhanced hypothalamic inflammation.MethodsThe present data show that leptin receptor-deficient (db/db) mice exhibit reduced hypothalamic SST neurons, particularly in the periventricular nucleus. We model this finding, using adeno-associated virus delivery of diphtheria toxin subunit A (DTA) driven by an SST-cre system to deplete these neurons in Sstcre/gfp mice (SST-DTA).ResultsSST-DTA mice exhibit enhanced hypothalamic c-Fos expression and brain inflammation as demonstrated by microglial and astrocytic activation. Bone marrow from SST-DTA mice undergoes skewed haematopoiesis, generating excess granulocyte-monocyte progenitors and increased proinflammatory (C-C chemokine receptor type 2; CCR2hi) monocytes. SST-DTA mice exhibited a 'diabetic retinopathy-like' phenotype: reduced visual function by optokinetic response (0.4 vs 0.25 cycles/degree; SST-DTA vs control mice); delayed electroretinogram oscillatory potentials; and increased percentages of retinal monocytes. Finally, mesenteric visceral adipose tissue from SST-DTA mice was resistant to catecholamine-induced lipolysis, displaying 50% reduction in isoprenaline (isoproterenol)-induced lipolysis compared with control littermates. Importantly, hyperglycaemia was not observed in SST-DTA mice.Conclusions/interpretationThe isolated reduction in hypothalamic SST neurons was able to recapitulate several hallmark features of type 2 diabetes in disease-relevant tissues.

Haemoplasmosis is a bacterial infection in erythrocytes caused by Mycoplasma sp. This study aimed to report methods of diagnosis, therapy, and evaluation of therapy in cats with haemoplasmosis. The cat showed decreased appetite, conjunctivitis, presence of mucoid mucus on the eyes and nose, gum anemia with a capillary refill time of more than 2 seconds, high temperature, and weakness. Skin and hair examination reported infestations of Ctenocephalides felis and Lynxacarus sp. on the hair. Routine hematologic examination showed normochromic normocytic anemia, leukocytosis, neutrophilia, eosinophilia, lymphocytosis, monocytosis, and hypoalbuminemia. A blood test examination observed Mycoplasma sp. in erythrocyte cells so the cat was diagnosed with haemoplasmosis. Treatment was performed using Oxytetracycline long-acting at 20 mg/kg BW intramuscularly for 2 weeks and revealed support to recovery during the treatment period. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic, caused by SARS-CoV-2, has posed significant health challenges worldwide. While children generally experience less severe illness compared to adults, pneumonia remains a substantial risk, particularly for those under five years old. This study examines the clinical characteristics and treatment outcomes of pediatric COVID-19 pneumonia patients treated with favipiravir in Thailand, aiming to identify associated factors for pneumonia. A retrospective review was performed on pediatric patients aged 1 month to 18 years hospitalized with COVID-19 at Srinagarind Hospital, Khon Kaen University, from 13 January 2020 to 15 November 2021. Data on demographics, clinical symptoms, treatment, and outcomes were collected, and logistic regression analysis was used to identify factors associated with pneumonia. Among 349 hospitalized children, the median age was 8 years, with 51.9% being male. Symptoms included a fever (100%), a cough (74.2%), and a rash (24.9%). COVID-19 pneumonia was diagnosed in 54.7% of the children. Favipiravir was administered as the standard treatment, showing mild adverse effects, including a rash (4.3%) and nausea (2.8%). Monocytosis was significantly associated with COVID-19 pneumonia (aOR 30.85, 95% CI: 9.03–105.41, p < 0.001), with an ROC curve area of 0.77 (95% CI: 0.71–0.83). Pediatric COVID-19 patients typically exhibit mild-to-moderate symptoms, with pneumonia being common in the early pandemic phase. Monocytosis is a significant factor associated with COVID-19 pneumonia. Favipiravir demonstrated mild adverse effects. Further studies are needed to validate these findings across different settings and phases of the pandemic.

CMML is a rare clonal myeloid neoplasm belonging to the myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) group characterized by persistent peripheral blood monocytosis. It is commonly seen in old age and has a varied clinical presentation. A critical morphological identification and distinction between monocyte precursors is very crucial for accurate morphological diagnosis and classification of MDS/MPN disorders in particular at centers lacking facilities for molecular and cytogenetic studies. We, therefore, present a rare case of a 5-year-old male diagnosed with CMML-2. [ABSTRACT FROM AUTHOR]

INTRODUCTION: In India, there is a high burden of infections such as tuberculosis, dengue, and malaria which are common causes of monocytosis. This increases the workload of smear examination by the pathologist. "Mono-dysplasia score" is obtained with a simple complete blood count on an automated cell counter and includes the parameters neutrophil (Ne) and monocyte (Mo) count and Ne-WX which is a Ne dispersion parameter. It is operator independent, objective, and does not require a high level of expertise. AIMS: The aims of the study were to assess the utility of Monoscore/mono-dysplasia score calculated using research parameters of Sysmex XN automated cell counter, as a screening tool for differentiating reactive monocytosis from hematological malignancies associated with monocytosis. MATERIALS AND METHODS: Samples sent in EDTA vacutainer for routine hemogram fulling the criteria for monocytosis (WHO criteria - absolute monocyte count =1 × 109/L and accounting for =10% of the total white blood cell count) were included in the study. Monoscore was calculated using the formula established by Schillinger et al. Flow cytometry, bone marrow examination, etc., were done as and when needed as standard-of-care tests to establish a final diagnosis. RESULTS: One thousand two hundred and fifty-seven samples were analyzed out of which 41 samples were chronic myelomonocytic leukemia and 126 were other hematological malignancies (HD) including acute leukemias, myelodysplastic syndrome, myeloproliferative neoplasm, etc. Using receiver operating characteristics curves, we established the cutoff 0.212 which showed a sensitivity of 97.6% and specificity of 96.4% to differentiated reactive monocytosis form HD. CONCLUSIONS: A sample showing monocytosis and Monoscore <0.212 and without any other flags can be safely auto-authorized without peripheral blood smears examination, reducing the burden of slides to be reviewed. [ABSTRACT FROM AUTHOR]

INTRODUCTION: In India, there is a high burden of infections such as tuberculosis, dengue, and malaria which are common causes of monocytosis. This increases the workload of smear examination by the pathologist. “Mono-dysplasia score” is obtained with a simple complete blood count on an automated cell counter and includes the parameters neutrophil (Ne) and monocyte (Mo) count and Ne-WX which is a Ne dispersion parameter. It is operator independent, objective, and does not require a high level of expertise. AIMS: The aims of the study were to assess the utility of Monoscore/mono-dysplasia score calculated using research parameters of Sysmex XN automated cell counter, as a screening tool for differentiating reactive monocytosis from hematological malignancies associated with monocytosis. MATERIALS AND METHODS: Samples sent in EDTA vacutainer for routine hemogram fulling the criteria for monocytosis (WHO criteria – absolute monocyte count ≥1 × 109/L and accounting for ≥10% of the total white blood cell count) were included in the study. Monoscore was calculated using the formula established by Schillinger et al. Flow cytometry, bone marrow examination, etc., were done as and when needed as standard-of-care tests to establish a final diagnosis. RESULTS: One thousand two hundred and fifty-seven samples were analyzed out of which 41 samples were chronic myelomonocytic leukemia and 126 were other hematological malignancies (HD) including acute leukemias, myelodysplastic syndrome, myeloproliferative neoplasm, etc. Using receiver operating characteristics curves, we established the cutoff 0.212 which showed a sensitivity of 97.6% and specificity of 96.4% to differentiated reactive monocytosis form HD. CONCLUSIONS: A sample showing monocytosis and Monoscore

Introduction Myelodysplastic syndromes (MDS) predominantly present with varying degrees of cytopenia, while myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) exhibit proliferative features. Genetic defects underlying different complete blood count (CBC) alterations remain to be defined.Objective We aimed to evaluate mutations and impacts on abnormal blood counts in MDS and MDS/MPN.Method MDS and MDS/MPN patients were recruited and sequenced by targeted next-generation sequencing. Clinical parameters, especially CBC, were evaluated for the association with genetic abnormalities and clinical outcomes.Results A total of 168 patients with myeloid neoplasms were recruited (92 cases of low-risk MDS, 57 cases of high-risk MDS and 19 cases of MDS/MPN). Compared to low-risk MDS and MDS/MPN, patients with high-risk MDS were presented with more severe neutropenia with 17.5% showing absolute neutrophil counts (ANC) lower than 0.5 × 109/L. Patients with MDS/MPN more commonly harboured mutations and had a higher number of mutations per case than low-risk MDS (94.7% vs. 56.5%; p

Simple Summary: Canine leishmaniasis and cardiopulmonary dirofilariasis are common parasitoses in dogs and are endemic in various regions of Italy. Although Leishmania infantum and Dirofilaria immitis have commonly been reported as single infections in dogs in Italy, mixed infection with both parasites is seldom reported. This case report describes a very rarely reported localization of Dirofilaria immitis microfilariae in the bone marrow of an adult dog, which was serologically and PCR-positive for Leishmania infantum. This is the second reported case of the localization of D. immitis microfilariae in the bone marrow of a Leishmania-infected dog. We report a rare and interesting case of mixed infection with Leishmania infantum and Dirofilaria immitis associated with the incidental finding of microfilariae in the bone marrow of a 9-year-old, intact, male Bullmastiff which was seropositive to L. infantum. Clinical signs showed progressive weakness, pale mucosae membranes, and a very low body condition score. Laboratory abnormalities included moderate, normocytic, normochromic, non-regenerative anemia; mild leukocytosis, neutrophilia, monocytosis, and eosinopenia; low platelet count; elevated C reactive protein; mild hyperkalemia, hypoalbuminemia, and hyperbeta-2-globulinemia; and a low A/G ratio. Hypoadrenocorticism, euthyroid sick syndrome, and alteration in the fibrinolytic phase of hemostasis were also detected. Microfilariae were incidentally found in bone marrow cytology aspirate in the absence of clinical features indicative of co-infection with D. immitis. PCR confirmed the identification of the Dirofilaria species. It is assumed that the microfilariae may have left the microcirculation and migrated to bone marrow tissues by crossing the vessel wall. To the best of our knowledge, only one such case has been previously reported in dogs. [ABSTRACT FROM AUTHOR]

Fluoxetine is an antidepressant that has multiple mechanisms of action and belongs to the group of selective serotonin reuptake inhibitors. The drug has been used for the management of severe mental depression and clinical trials for other indications, including obsessive–compulsive disorder and a wide profile of related disorders. Twenty male Wistar rats were treated with two different doses of fluoxetine: 1 mg/mL (lower dose, Fluox L) and 3 mg/mL (higher dose, Fluox H) for 1 week. After the treatment, the researcher analyzes hematological and behavioral changes. A lower dose causes a decrease in erythrocyte count (RBC) and an increase in hemoglobin (HB), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC). The high dose led to an increase in RBC and a decrease in HB, mean cell volume (MCV), MCH, and MCHC. Hematological changes indicate the development of eryptosis and possible anemia. Variations in leukocyte indicators, such as a significant decrease in leukocyte counts (WBC), lymphocytes, segmented neutrophils, and an increase in the number of monocytes, indicate altered immune response, the occurrence of neutropenia, and severe monocytosis. Behavioral patterns such as depression, disorientation, and aggressiveness are more frequent at high doses. The presence of hyperglycemia indicates the development of a stress reaction. Treatment with a lower dose of fluoxetine can cause hematological disorders in case of long-term use of the drug, and a high dose of the drug can cause acute hematological changes. [ABSTRACT FROM AUTHOR]

The article focuses on cases of severe dysplasia with aberrant neutrophil morphology misclassified as monocytosis by the Sysmex XN haematological analyser and DI-60 digital morphology system. Topics include the diagnostic significance of cellular dysplasia in myelodysplastic syndromes, the presentation of two cases with misleading results, and the challenges in automated cell classification systems.

Congenital syphilis (CS), a common but forgotten disease has a broad spectrum of clinical presentation. Vertical transmission of this spirochaetal infection from the pregnant mother to the foetus can result in varied manifestations ranging from asymptomatic infection to lifethreatening conditions in the form of stillbirth and neonatal death. The haematological and visceral manifestations of this disease can closely mimic various conditions including haemolytic anaemia and malignancies. Congenital syphilis should be considered as a differential in any infant presenting with hepatosplenomegaly and haematological abnormalities even if the antenatal screen was negative. We report a 6-monthold infant with congenital syphilis presenting with organomegaly, bicytopenia and monocytosis. A strong index of suspicion and early diagnosis is the key to the good outcome as treatment is simple and cost-effective. [ABSTRACT FROM AUTHOR]

The prognostic impact of monocytosis has not yet been determined in patients with myelodysplastic syndromes (MDS). We examined absolute monocyte counts in the peripheral blood at the time of diagnosis in 1949 patients with a bone marrow blast count < 5%, a condition we call MDS < EB1 (MDS with a blast percentage lower than that of MDS with excess blasts 1, according to the WHO classification). Monocytosis (> 600/µl) was associated with higher median hemoglobin, WBC, and ANC, and more favorable karyotype (p =.001). Nevertheless, monocytosis was associated with shorter overall survival (OS) (108 vs. 126 months, p =.002) and earlier transformation into AML (p <.001). In patients with sideroblastic phenotype, the percentage of ring sideroblasts significantly correlated with the monocyte count (p =.005), and OS was significantly shorter when monocytosis was documented (88 vs. 132 months, p =.004). The survival disadvantage of patients with MDS < EB1 and peripheral blood monocytosis suggests that these patients suffer from a CMML-like disease. Even though they are generally classified as MDS with persistent monocytosis, such patients should be considered candidates for therapeutic options employed in CMML. [ABSTRACT FROM AUTHOR]

A 3-month-old kitten weighing 1.05 kg was presented to the University veterinary hospital at Kokkalai in Thrissur district of Kerala, India, with the complaint of open-mouth breathing, lethargy and complete anorexia for the past three days, and weight loss. Detailed clinical examination revealed inspiratory dyspnoea without stridor, tachypnoea, muffled lung and heart sounds on auscultation, pale mucous membrane, and weak pulse. Haematology revealed leukocytosis with granulocytosis and monocytosis. Thoracic radiography, ultrasonography and thoracocentesis confirmed pyothorax. Microbial culture of thoracic aspirate revealed heavy growth of Acinetobacter spp. The cat responded to parenteral therapy with ceftiofur followed by cefixime orally for 21 days. Doxycycline was prescribed for concurrent mycoplasmosis. Thoracic radiograph 10 days later revealed a significant reduction in pleural fluid. A review of the case two months later found that the kitten recovered uneventfully. A rare case of Acinetobacter spp. associated pyothorax and its medical management in a cat is reported. The clinical manifestations, radiographic changes and ultrasonographic findings were discussed. [ABSTRACT FROM AUTHOR]

Abstract Background Systemic lupus erythematosus (SLE), an autoimmune disorder that damages various organ systems, is caused by a combination of genetic and environmental factors. Although germline mutations of several genes are known to cause juvenile SLE, most of the susceptibility genetic variants of adult SLE are common variants of the population, somatic mutations that cause or exacerbate SLE have not been reported. We hereby report a refractory SLE case with monocytosis accompanying somatic KRAS mutation that have been shown to cause lupus-like symptoms. Case presentation A 60-year-old female patient who had been diagnosed with SLE was admitted to our hospital. Although prednisolone and tacrolimus treatments had kept her thrombocytopenia and anti-DNA Ab level at bay for more than 4 years, a diagnosis of transverse myelitis was made when she became acutely ill with pleocytosis. Elevated cells (predominately monocytes), protein, IgG, and IL-6 levels were also found in the cerebrospinal fluid (CSF) of the patient. Standard pulse treatments of methylprednisolone, high-dose of prednisolone, and intravenous cyclophosphamide in combination with plasma exchange could not alleviate the refractory neural and autoimmune manifestation. Monocytosis of peripheral blood was also noted. Flow cytometric analysis revealed elevated ratio of CD14+CD16+ atypical monocytes, which excluded the possibility of chronic myelomonocytic leukemia. Lupus-like symptoms with monocytosis reminded us of Ras-associated autoimmune leukoproliferative disorder, and Sanger sequencing of KRAS and NRAS genes from the patients’ peripheral blood mononuclear cells (PBMC), sorted CD3+ lymphocytes and CD14+ monocytes, and cerebrospinal fluid were performed. An activating KRAS somatic mutation was found in the patients’ DNA at the time of encephalomyelitis diagnosis. Conclusion Somatic mutations of some genes including KRAS may cause the refractoriness of SLE.

Chronic myeloid leukemia (CML) and chronic myelomonocytic leukemia (CMML) are two common myeloid neoplasms with overlapping morphologic features. We report a patient initially diagnosed with CML and treated with Tyrosine kinase inhibitor (TKI) but who then developed persistent monocytosis and worsening thrombocytopenia one year later. Repeat bone marrow biopsies only showed CML at the molecular level. However, markedly hypercellular bone marrow, megakaryocytic dysplasia, and SRSF2, TET2, and RUNX1 mutations by NextGen sequencing pointed to a diagnosis of CMML. For CML patients with persistent monocytosis and cytopenia, a mutational profile by NGS is helpful to exclude or identify the coexisting CMML.

Myelodysplastic syndromes (MDS) predominantly present with varying degrees of cytopenia, while myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) exhibit proliferative features. Genetic defects underlying different complete blood count (CBC) alterations remain to be defined. We aimed to evaluate mutations and impacts on abnormal blood counts in MDS and MDS/MPN. MDS and MDS/MPN patients were recruited and sequenced by targeted next-generation sequencing. Clinical parameters, especially CBC, were evaluated for the association with genetic abnormalities and clinical outcomes. A total of 168 patients with myeloid neoplasms were recruited (92 cases of low-risk MDS, 57 cases of high-risk MDS and 19 cases of MDS/MPN). Compared to low-risk MDS and MDS/MPN, patients with high-risk MDS were presented with more severe neutropenia with 17.5% showing absolute neutrophil counts (ANC) lower than 0.5 × 109/L. Patients with MDS/MPN more commonly harboured mutations and had a higher number of mutations per case than low-risk MDS (94.7% vs. 56.5%; p < 0.001 and 3 vs. 1; p < 0.001, respectively). Patients with SF3B1 mutations showed lower haemoglobin levels than wild-type (7.9 vs. 8.4 g/dL, p = 0.02), but were associated with normal platelet counts (286 vs. 93 × 109/L; p < 0.001). Patients with U2AF1 mutations were associated with more severe leukopenia than wild-type (3 vs. 4.18 × 109/L; p = 0.02). KRAS mutations were associated with monocytosis (p < 0.001). Multivariate analysis revealed high-risk MDS, MDS/MPN, severe neutropenia (ANC < 0.5 × 109/L), and mutations in ASXL1 and SETBP1 were associated with inferior survival outcomes. Certain mutations were related to more severe anaemia, lower white blood cell count or monocytosis in Asian MDS and MDS/MPN patients. [ABSTRACT FROM AUTHOR]

Clonal monocytosis reflects a preneoplastic or neoplastic sustained increase in the absolute monocyte count in the absence of reactive causes. Causes of clonal monocytosis include clonal cytopenias with monocytosis and acute and chronic myeloid neoplasms. Chronic myelomonocytic leukemia is a prototypical myelodysplastic/myeloproliferative overlap neoplasm in adults, characterized by sustained peripheral blood monocytosis. Kidney abnormalities, including acute kidney injury and chronic kidney disease, are frequent in patients with chronic myelomonocytic leukemia and are predictors of worse outcomes. In addition, acute kidney injury/chronic kidney disease often limits eligibility for allogeneic stem cell transplantation or enrollment in clinical trials. In this review, we highlight clonal monocytosis-related etiologies that give rise to acute kidney injury and chronic kidney disease, with special emphasis on chronic myelomonocytic leukemia and lysozyme-induced nephropathy. Monocytes produce lysozyme, which, in excess, can accumulate in and damage the proximal renal tubular epithelium. Early identification of this etiology and a timely reduction in monocyte counts can salvage kidney function. Other etiologies of kidney injury associated with clonal monocytosis include direct renal infiltration by monocytes, renal extramedullary hematopoiesis, myeloproliferative neoplasm-associated glomerulopathy, autoimmune (membranous nephropathy, minimal change disease) and paraneoplastic manifestations, thrombotic microangiopathy, obstructive nephropathy due to myeloproliferation, and urate nephropathy due to tumor lysis syndrome. We propose to group these mechanistic etiologies of kidney injury as clonal monocytosis of renal significance and provide guidance on their diagnosis and management., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Despite the relatively rare comorbidity with bacterial infections, in most cases treatment of COVID-19-associated pneumonia is accompanied by empirical antibiotic therapy. In addition, the occurrence of leukocytosis in response to glucocorticosteroid (GCS) therapy is often perceived as comorbid bacterial flora and is a reason for initiating antibiotic therapy. Therefore, an urgent task is to properly interpret leukocytosis in response to GCS therapy in COVID-19. The aim of the study was to examine dynamic changes in count of venous blood leukocytes, neutrophils and monocytes in patients with moderate COVID-19 after systemic GCS. We analyzed parameters of complete blood count in 154 patients with verified moderate COVID-19, at the Temporary Infectious Diseases Hospital, the “Patriot” Park of the Moscow Region. The comparison group (I) consisted of 128 patients without clinical signs of bacterial infection and leukocytosis observed on admission, who were prescribed GCS therapy. The control group (II) consisted of 26 subjects showing on admission signs of bacterial infection — a cough with purulent sputum combined with neutrophilic leukocytosis. The dynamics in venous blood cell count was assessed in group I of patients before the onset, 3 and 6 days after beginning GCS therapy. We also compared count of leukocytes, neutrophils and monocytes between patients with developed leukocytosis in group I vs. group II. As a result, an increased count of leukocytes, neutrophils and monocytes was revealed according to assessing complete blood count test in patients from group I on days 3 and 6 of ongoing GCS therapy. All patients with developed leukocytosis after GCS admission (103 subjects) had no clinical signs of bacterial infection. Patients with developed leukocytosis from group I had increased count of monocytes (0.90 (0.84; 1.02) on day 3 after GCS onset and 0.94 (0.87; 1.26) on day 6 of GCS) compared with group II (0.61 [0.50; 0.71]), p 0.001. The inter-group count of leukocytes and neutrophils did not differ. Monocytosis after GCS therapy may serve as a differential diagnostic criterion to distinguish between glucocorticoid-induced leukocytosis and comorbid bacterial infection. This may be one of the factors influencing a decision to prescribe antibiotic therapy.

Cytomegalovirus (CMV) syndrome and infectious disease are defined as pathogen detection with appropriate clinical symptoms, but there are not pathognomonic signs of CMV disease. Although the prodrome of acute minor viral infections leukopenia (lymphopenia and neutropenia) is noted with onset of fever, followed by monocytosis, the role of monocytosis in CMV disease has not been described. Furthermore, under influence of corticosteroid therapy, CMV reactivation and monocytosis are described, but without a strict relationship with steroids dose. In the study, the monocyte level was investigated during the CMV infectious process. Regrettably, a non-selected group of 160 patients with high CMV viremia showed high dispersion of monocyte level and comparable with the median value for healthy subjects. Therefore, we investigated monocyte level in CMV-infected patients in relation to the logarithmic phase of the infectious process. Samples from patients with active CMV replication (exponential growth of CMV viremia) were tested. Significant monocytosis (above 1200/µL) during the logarithmic phase of CMV infection (with exponent between 3.23 and 5.77) was observed. Increased count and percentage of monocytes correlated with viral replication in several clinical situations except when there was a rapid recovery without relapse. Furthermore, glucocorticoids equivalent to 10 and 20 mg of dexamethasone during a 2–3-week period caused monocytosis—significant increase (to 1604 and 2214/µL, respectively). Conclusion: In light of the logarithmic increase of viral load, high monocytosis is a hallmark of CMV replication. In the COVID-19 era, presence of high virus level, especially part of virome (CMV) in the molecular technique, is not sufficient for the definition of either proven or probable CMV replication at any site. These preliminary observations merit additional studies to establish whether this clinical response is mediated by monocyte production or by decrease of differentiation to macrophages. [ABSTRACT FROM AUTHOR]

A 9‐month‐old Beagle presented with a 24‐hour history of lethargy, pyrexia, and cervical and thoracolumbar pain. Cranial nerve examination revealed an absent menace response, an absent dazzle reflex, and absent direct and left‐to‐right consensual pupillary light reflexes in the left eye, indicating a non‐visual eye. Funduscopic examination and electroretinography were unremarkable. Complete blood profile showed moderate neutrophilia, monocytosis and elevated C‐reactive protein. Cerebrospinal fluid analysis revealed a neutrophilic pleocytosis. Magnetic resonance imaging of the head, thoracic and abdominal imaging, urinalysis, joint taps and infectious disease titres were unremarkable. A diagnosis of steroid‐responsive meningitis arteritis (SRMA) with left optic nerve involvement was concluded. Blindness has not been reported in cases with SRMA. An extension of the leptomeningeal inflammation into the optic nerve sheaths is hypothesized as the underlying pathophysiology. SRMA should be considered as a cause of blindness in the presence of other clinical signs compatible with this condition. [ABSTRACT FROM AUTHOR]

Biallelic changes in the ZNFX1 gene have been recently reported to cause severe familial immunodeficiency. Through a search of our bio/databank with information from genetic testing of >55 000 individuals, we identified nine additional patients from seven families with six novel homozygous ZNFX1 variants. Consistent with the previously described phenotype, our patients suffered from monocytosis, thrombocytopenia, hepatosplenomegaly, recurrent infections, and lymphadenopathy. The two most severely affected probands also had renal involvement and clinical presentations compatible with hemophagocytic lymphohistiocytosis. The disease was less lethal among our patients than previously reported. We identified two missense changes, two variants predicted to result in complete protein loss through nonsense‐mediated decay, and two frameshift changes that likely introduce a truncation. Our findings (i) independently confirm the role of ZNFX1 in primary genetic immunodeficiency, (ii) expand the genetic and clinical spectrum of ZNFX1‐related disease, and (iii) illustrate the utility of large, well‐curated, and continually updated genotype–phenotype databases in resolving molecular diagnoses of patients with initially negative genetic testing findings. [ABSTRACT FROM AUTHOR]

Purpose of Review: Myeloproliferative neoplasms (MPN) are a heterogeneous group of hematopoietic stem cell neoplasms comprising of polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) that share driver mutations (JAK2/CALR/MPL) resulting in constitutive activation of JAK/STAT and other signaling pathways. Patients with MPN have shortened survival and an inherent risk for leukemic evolution. Prognostically relevant clinical and genetic parameters have been incorporated into mutation-enhanced scoring systems (MIPSS70-plus version 2.0, MIPSS-ET/PV). In the current review, we describe clinical and pathological features along with prognostic significance of MPN with monocytosis. Recent Findings: Monocytosis, defined by an absolute monocyte count (AMC) ≥ 1 × 10 9/L, is a typical manifestation of chronic myelomonocytic leukemia (CMML) but is also associated with 21% and 17% of PV and PMF patients, respectively. Recent studies on the subject have reported that MPN patients with monocytosis are older and present with concomitant leukocytosis. In regard to PV, patients with monocytosis harbor unfavorable cytogenetic abnormalities including +8, 7/7q, i(17q), 5/5q−,12p−, inv(3), or 11q23 rearrangement and SRSF2 mutations, whereas PMF patients with monocytosis had significant thrombocytopenia, higher circulating blasts, higher symptom burden, and ASXL1 mutations. Moreover, presence of monocytosis predicted inferior survival in both PV and PMF. Summary: Monocytosis in MPN is associated with a distinct clinical and genetic profile and may serve as a marker of aggressive disease biology. [ABSTRACT FROM AUTHOR]

Joseph Baruch Baluku,1– 3 Joseph Musaazi,4 Rose Mulwana,1 Araali Robert Mugabo,1 Felix Bongomin,5 Winceslaus Katagira3 1Mulago National Referral Hospital, Pulmonology Division, Kampala, Uganda; 2Mildmay Uganda, Kampala, Uganda; 3Makerere University Lung Institute, Kampala, Uganda; 4Makerere University Infectious Disease Institute, Kampala, Uganda; 5Department of Medical Microbiology & Immunology, Faculty of Medicine, Gulu University, Gulu, UgandaCorrespondence: Joseph Baruch BalukuMulago National Referral Hospital, Pulmonology Division, P.O. Box 7051, Kampala, UgandaTel +256706327972Email bbjoe18@gmail.comPurpose: CD4+ T-lymphocytopenia is a risk for tuberculosis (TB) infection, reactivation and severe disease. We sought to determine the prevalence and predictors of CD4 T-lymphocytopenia among HIV-negative patients with bacteriologically confirmed TB in Uganda.Patients and Methods: Eligible participants were adult HIV-negative patients with bacteriologically confirmed TB at the National TB Treatment Centre in Uganda. CD4+ and CD8+ T-lymphocyte counts were determined by flow cytometry. We defined CD4+ T-lymphocytopenia as a CD4+ T-lymphocyte count of < 418 cells/mm3 as per the population estimate for Ugandans. We performed logistic regression analysis to determine predictors of CD4+ T-lymphocytopenia.Results: We enrolled 216 participants whose mean age (standard deviation (±SD)) was 32.5 (± 12.1) years, of whom 146 (67.6%) were males. The prevalence of CD4+ T-lymphocytopenia was 25% (54/216) (95% confidence interval (CI): 19.6– 31.2%). Patients with anaemia (adjusted odds ratio (aOR): 3.83, 95% CI: 1.59– 9.23, p = 0.003), weight loss (aOR: 3.61, 95% CI: 1.07– 12.23, p = 0.039) and a low CD8+ T-cell count (aOR: 6.10, 95% CI: 2.68– 13.89, p < 0.001) were more likely to have CD4+ T-lymphocytopenia while those with monocytosis (aOR: 0.35, 95% CI: 0.14– 0.89, p = 0.028) were less likely to have CD4+ T-lymphocytopenia.Conclusion: There was a high prevalence of CD4+ T-lymphocytopenia among HIV-negative TB patients. Patients with weight loss, anaemia and a low CD8+ count were more likely to have CD4+ T-lymphocytopenia while those with monocytosis were less likely to have CD4+ lymphocytopenia. The findings suggest that CD4+ lymphocytopenia is indicative of severe disease and globally impaired cell-mediated immune responses against TB.Keywords: HIV negative, tuberculosis, CD4+, CD8+, lymphoctyopenia, monocytosis, weight loss, anaemia

Osteosarcoma is a common neoplastic condition of the bone mostly affecting the appendicular bones in dogs. A five-year-old female Rottweiler was presented with a swollen left hind limb. Haematology showed mild nonregenerative anaemia, severe leukocytosis, and moderate neutrophilia without left shift, monocytosis, and severe lymphopenia. Fine needle aspirate (FNA) cytology revealed oval to spindle cells with marked cellular pleomorphism, anisocytosis, binucleation, and proteinaceous granules in the background while radiographic examination revealed osteolysis of the tibia and fibular with new bone formation. These findings are consistent with osteosarcoma. A diagnosis of osteosarcoma was made, based on the cytology and radiography. Surgical amputation of the complete left limb was carried out. However, the dog died of leptospirosis one month later. Post mortem examination revealed pulmonary metastasis of the osteosarcoma. Histopathology of the limb growth revealed oval to spindle cells with intracytoplasmic eosinophilic materials and osteoid matrix. Diagnosis and treatment of dogs affected by osteosarcoma should be comprehensive and complete, with adequate follow-up. The marked lymphopenia could be associated with poor prognosis, therefore an index for prognosis in osteosarcoma. The mortality, in this case, could have been related to leptospirosis and associated with the immunosuppression from tumour metastasis. [ABSTRACT FROM AUTHOR]

Abstract Rare cases of CML present with monocytosis as well as morphologic dysplasia and harbor p210BCR‐ABL1. Cytogenetic and molecular studies must be performed to confirm the diagnosis of this kind of CML.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm with the molecular hallmark of BCR-ABL1 chimeric transcripts from t(9;22)(q24;q22). In more than 95% of CML, the fusion occurs in the major breakpoint cluster region (M-bcr) of BCR, most commonly producing the e14a2 or e13a2 type. CML with e1a2 BCR-ABL1 by fusion in minor bcr is rare, accounting for approximately 1% of CML. CML with e1a2 BCR-ABL1 is reportedly associated with monocytosis and poor prognosis. Here we describe a woman who underwent bone marrow (BM) study with an impression of chronic myelomonocytic leukemia based on thrombocytosis and prominent monocytosis. Genetic workup revealed, however, t(9;22) and e1a2 BCR-ABL1, which indicated CML and explained her unusual monocytosis. A review of serial complete blood counts (CBC) before the BM study demonstrated that isolated monocytosis preceded the abnormalities in other parameters of CBC. The patient is on follow-up with tyrosine kinase inhibitor (TKI, dasatinib) medication. Close monitoring is required due to the association of e1a2 BCR-ABL1 with poor response to TKI and frequent disease progression. Timely genetic workup and determination of the precise type of BCR-ABL1 transcripts are critical for the diagnosis and stratification of this rare subtype of CML with distinct genotype-phenotype correlations.

Purpose of Review: In this review, we provide a comprehensive and contemporary understanding of malignant monocytosis and provide a framework by which the appropriate diagnosis with malignant monocytosis can be rendered. Recent Findings: Increasing data support the use of molecular data to refine the diagnostic approach to persistent monocytosis. The absence of a TET2, SRSF2, or ASXL1 mutation has ≥ 90% negative predictive value for a diagnosis of CMML. These data may also reliably differentiate chronic myelomonocytic leukemia, the malignancy that is most associated with mature monocytosis, from several other diseases that can be associated with typically a lesser degree of monocytosis. These include acute myelomonocytic leukemia, acute myeloid leukemia with monocytic differentiation, myelodysplastic syndromes, and myeloproliferative neoplasms driven by BCR-ABL1, PDGFRA, PDGFRB, or FGFR1 rearrangements or PCM1-JAK2 fusions among other rarer aberrations. The combination of monocyte partitioning with molecular data in patients with persistent monocytosis may increase the predictive power for the ultimate development of CMM but has not been prospectively validated. Summary: Many conditions, both benign and malignant, can be associated with an increase in mature circulating monocytes. After reasonably excluding a secondary or reactive monocytosis, there should be a concern for and investigation of malignant monocytosis, which includes hematopathologic review of blood and marrow tissues, flow cytometric analysis, and cytogenetic and molecular studies to arrive at an appropriate diagnosis. [ABSTRACT FROM AUTHOR]

Purpose of Review: Monocytosis is a distinct but non-specific manifestation of various physiologic and pathologic conditions. Among hematopoietic stem cell neoplasms, depending on the criteria used for disease classification, monocytosis may be a consistent and integral component of diseases such as chronic myelomonocytic leukemia or acute myeloid leukemia with monocytic differentiation, or it may represent an inconsistent finding that often provides a clue to the underlying genetic changes driving the neoplasm. The purpose of this review is to provide the readers with a laboratory-based approach to neoplastic monocytosis. Recent Findings: In-depth elucidation of the genomic landscape of myeloid neoplasms within the past few years has broadened our understanding of monocytosis and its implications for diagnosis and prognosis. Genetic findings also shed light on potential disease response — or lack thereof — to various therapeutic agents used in the setting of myeloid neoplasms. Summary: In this review, we provide our approach to diagnose neoplastic monocytosis in the context of case-based studies while incorporating the most recent literature on this topic. [ABSTRACT FROM AUTHOR]

Purpose of Review: Monocytosis is a frequently encountered clinical condition that needs appropriate investigation due to a broad range of differential diagnoses. This review is meant to summarize the latest literature in the diagnostic testing and interpretation and offer a stepwise diagnostic approach for a patient presenting with monocytosis. Recent Findings: Basic studies have highlighted the phenotypic and functional heterogeneity in the monocyte compartment. Studies, both translational and clinical, have provided insights into why monocytosis occurs and how to distinguish the different etiologies. Flow cytometry studies have illustrated that monocyte repartitioning can distinguish chronic myelomonocytic leukemia, a prototypical neoplasm with monocytosis from other reactive or neoplastic causes. Summary: In summary, we provide an algorithmic approach to the diagnosis of a patient presenting with monocytosis and expect this document to serve as a reference guide for clinicians. [ABSTRACT FROM AUTHOR]

Purpose of Review: Juvenile myelomonocytic leukemia (JMML) is a rare but severe pediatric neoplasm with hematopoietic stem cell transplant as its only established curative option. The development of targeted therapeutics for JMML is being guided by an understanding of the pathobiology of this condition. Here, we review JMML with an emphasis on genetics in order to (i) demonstrate the relationship between JMML genotype and clinical phenotype and (ii) explore potential genetic targets of novel JMML therapies. Recent Findings: DNA hypermethylation studies have demonstrated consistently that methylation is related to disease severity. Increasing understanding of methylation in JMML may open the door to novel therapies, such as DNA methyltransferase inhibitors. The PI3K/AKT/MTOR, JAK/STAT, and RAF/MEK/ERK pathways are being investigated as therapeutic targets for JMML. Summary: Future therapy for JMML will be driven by an increased understanding of pathobiology. Targeted therapeutic approaches hold potential for improving outcomes in patients with JMML. [ABSTRACT FROM AUTHOR]

Chronic myelomonocytic leukemia (CMML) is a hematologic malignancy characterized by absolute monocytosis, one or more lineage dysplasia, and proliferative features including myeloid hyperplasia, splenomegaly, and constitutional symptoms. Because of vast clinical heterogeneity in presentation and course, risk stratification is used for a risk‐adapted treatment strategy. Numerous prognostic scoring systems exist, some of which incorporate mutational information. Treatment ranges from observation to allogeneic hematopoietic stem cell transplantation. Therapies include hydroxyurea for cytoreduction, hypomethylating agents, and the JAK1/2 inhibitor ruxolitinib to address splenomegaly and constitutional symptoms. Recently, oral decitabine with cedazuridine was approved and represents a convenient treatment option for CMML patients. Although novel therapeutics are in development for CMML, further work is needed to elucidate possible targets unique to the CMML clone. In this review, we will detail the pathophysiology, risk stratification, available treatment modalities, and novel therapies for CMML, and propose a modern treatment algorithm. Implications for Practice: Chronic myelomonocytic leukemia (CMML) is a clinically heterogenous disease, which poses significant management challenges. The diagnosis of CMML requires bone marrow biopsy and aspirate with thorough evaluation. Risk stratification and symptom assessment are essential to designing an effective treatment plan, which may include hypomethylating agents (HMAs) in intermediate or high‐risk patients. The recently approved oral decitabine/cedazuridine provides a convenient alternative to parenteral HMAs. Ruxolitinib may be effective in ameliorating proliferative symptoms and splenomegaly. Allogeneic stem cell transplantation remains the only treatment with curative potential; however, novel therapies are in clinical development which may significantly alter the therapeutic landscape of CMML. This review describes the current pathologic understanding of chronic myelomonocytic leukemia (CMML), appraises risk factors and stratification models, details treatment options, and proposes a contemporary treatment algorithm for patients with CMML. [ABSTRACT FROM AUTHOR]

Human inborn errors of IFN-α underlie mycobacterial disease, due to insufficient IFN-α production by lymphoid cells, impaired myeloid cell responses to this cytokine, or both. We report four patients from two unrelated kindreds with intermittent monocytosis and mycobacterial disease, including bacillus Calmette-Guérin-osis and disseminated tuberculosis, and without any known inborn error of IFN-α. The patients are homozygous for ZNFX1 variants (p.S959* and p.E1606Rfs*10) predicted to be loss of function (pLOF). There are no subjects homozygous for pLOF variants in public databases. ZNFX1 is a conserved and broadly expressed helicase, but its biology remains largely unknown. It is thought to act as a viral double-stranded RNA sensor in mice, but these patients do not suffer from severe viral illnesses. We analyze its subcellular localization upon overexpression in A549 and HeLa cell lines and upon stimulation of THP1 and fibroblastic cell lines. We find that this cytoplasmic protein can be recruited to or even induce stress granules. The endogenous ZNFX1 protein in cell lines of the patient homozygous for the p.E1606Rfs*10 variant is truncated, whereas ZNFX1 expression is abolished in cell lines from the patients with the p.S959* variant. Lymphocyte subsets are present at normal frequencies in these patients and produce IFN-α normally. The hematopoietic and nonhematopoietic cells of the patients tested respond normally to IFN-α. Our results indicate that human ZNFX1 is associated with stress granules and essential for both monocyte homeostasis and protective immunity to mycobacteria. [ABSTRACT FROM AUTHOR]

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Abstract Background Noonan syndrome is an autosomal dominant disorder secondary to RASopathies, which are caused by germ‐line mutations in genes encoding components of the RAS mitogen‐activated protein kinase pathway. RIT1 (OMIM *609591) was recently reported as a disease gene for Noonan syndrome. Methods and Results We present a patient with RIT1‐associated Noonan syndrome, who in addition to the congenital heart defect, had monocytosis, myeloproliferative disorder, and accelerated idioventricular rhythm that was associated with severe hemodynamic instability. Noonan syndrome was suspected given the severe pulmonary stenosis, persistent monocytosis, and “left‐shifted” complete blood counts without any evidence of an infectious process. Genetic testing revealed that the patient had a heterozygous c.221 C>G (pAla74Gly) mutation in the RIT1. Conclusion We report a case of neonatal Noonan syndrome associated with RIT1 mutation. The clinical suspicion for Noonan syndrome was based only on the congenital heart defect, persistent monocytosis, and myeloproliferative process as the child lacked all other hallmarks characteristics of Noonan syndrome. However, the patient had an unusually malignant ventricular dysrhythmia that lead to his demise. The case highlights the fact that despite its heterogeneous presentation, RIT1‐associated Noonan syndrome can be extremely severe with poor outcome.

With the increasing prevalence of diabetes worldwide, vascular complications of diabetes are also on the rise. Diabetes results in an increased risk of macrovascular complications, with atherosclerotic cardiovascular disease (CVD) being the leading cause of death in adults with diabetes. The exact mechanisms for how diabetes promotes CVD risk are still unclear, although it is evident that monocytes and macrophages are key players in all stages of atherosclerosis both in the absence and presence of diabetes, and that phenotypes of these cells are altered by the diabetic environment. Evidence suggests that at least five pro-atherogenic mechanisms involving monocytes and macrophages contribute to the accelerated atherosclerotic lesion progression and hampered lesion regression associated with diabetes. These changes include (1) increased monocyte recruitment to lesions; (2) increased inflammatory activation; (3) altered macrophage lipid accumulation and metabolism; (4) increased macrophage cell death; and (5) reduced efferocytosis. Monocyte and macrophage phenotypes and mechanisms have been revealed mostly by different animal models of diabetes. The roles of specific changes in monocytes and macrophages in humans with diabetes remain largely unknown. There is an ongoing debate on whether the changes in monocytes and macrophages are caused by altered glucose levels, insulin deficiency or insulin resistance, lipid abnormalities, or combinations of these factors. Current research in humans and mouse models suggests that reduced clearance of triglyceride-rich lipoproteins and their remnants is one important mechanism whereby diabetes adversely affects macrophages and promotes atherosclerosis and CVD risk. Although monocytes and macrophages readily respond to the diabetic environment and can be seen as protagonists in diabetes-accelerated atherosclerosis, they are likely not instigators of the increased CVD risk.

Introduction: Monocytosis Workflow Optimization rule set has been developed by using mono‐dysplasia‐score to determine reactive monocytosis and prevent unnecessary blood smear of these patients and for detection of chronic myelomonocytic leukemia cases during complete blood count. In our study, we aimed to examine the contribution of Monocytosis Workflow Optimization rule set. Methods: Adult patients with monocyte count ≥1.0 103/µL and monocyte percentage ≥10% were included in our study. Blood smears were made from the samples in our laboratory. These smears were examined and patients were divided into two groups as reactive monocytosis or hematological malignancy. The groups were compared in terms of Monocytosis Workflow Optimization rule set and device flags. Results: Twenty‐one patients had hematological malignancies of 155 patients who were included in our study. Monocytosis Workflow Optimization rule set suggested performing blood smear in 19 of the patients with hematological malignancy, and evaluated two patients as reactive monocytosis with 90.5% sensitivity and 76.9% specificity. There was an "abnormal lymphocyte/ blast" flag in 90.5% of patients with hematological malignancies and in patients whose Monocytosis Workflow Optimization rule set defined as reactive monocytosis and it was found that sensitivity and negative predictive value reached 100%. Conclusion: Automated validation support systems and softwares developed especially for these systems make it possible to classify patients with their non‐specific findings, as a result both contributing to the reduction of laboratory workload and costs and assisting laboratory specialists and clinicians with adding value to laboratory results. [ABSTRACT FROM AUTHOR]

Introduction: Chronic myelomonocytic leukemia (CMML) is a hematological malignancy that is extremely variable regarding its clinical course. It may present either as a chronic disorder with mild symptoms and low disease burden for several years, thereby justifying a watch-and-wait-strategy, or may soon progress to acute myeloid leukemia (AML) leaving allogeneic stem cell transplantation as the only curative treatment option.Areas Covered: Attempts have been made to integrate clinical, cytogenetic, and molecular parameters into scoring systems aiming at providing reliable prognostic information. In this article, we discuss several prognostic parameters and validate prognostic scores in a cohort of 645 patients with CMML.Expert Opinion: We show that the CPSS (CMML prognostic scoring system) is a useful prognostic tool. The integration of molecular data into the new CPSS-mol will further improve prognostic accuracy, primarily by identifying an increased proportion of higher-risk patients. [ABSTRACT FROM AUTHOR]

Background: Noonan syndrome is an autosomal dominant disorder secondary to RASopathies, which are caused by germ‐line mutations in genes encoding components of the RAS mitogen‐activated protein kinase pathway. RIT1 (OMIM *609591) was recently reported as a disease gene for Noonan syndrome. Methods and Results: We present a patient with RIT1‐associated Noonan syndrome, who in addition to the congenital heart defect, had monocytosis, myeloproliferative disorder, and accelerated idioventricular rhythm that was associated with severe hemodynamic instability. Noonan syndrome was suspected given the severe pulmonary stenosis, persistent monocytosis, and "left‐shifted" complete blood counts without any evidence of an infectious process. Genetic testing revealed that the patient had a heterozygous c.221 C>G (pAla74Gly) mutation in the RIT1. Conclusion: We report a case of neonatal Noonan syndrome associated with RIT1 mutation. The clinical suspicion for Noonan syndrome was based only on the congenital heart defect, persistent monocytosis, and myeloproliferative process as the child lacked all other hallmarks characteristics of Noonan syndrome. However, the patient had an unusually malignant ventricular dysrhythmia that lead to his demise. The case highlights the fact that despite its heterogeneous presentation, RIT1‐associated Noonan syndrome can be extremely severe with poor outcome. [ABSTRACT FROM AUTHOR]