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Impaired function of hematopoiesis after treatment with chimeric antigen T-cells (CAR-T) is a frequent finding and can interest a wide range of patients, regardless of age and underlying disease. Trilinear cytopenias, as well as hypogammaglobulinemia, B-cell aplasia, and T-cell impairment, can severely affect the infectious risk of CAR-T recipients, as well as their quality of life. In this review, we provide an overview of defects in hematopoiesis after CAR-T, starting with a summary of different definitions and thresholds. We then move to summarize the main pathogenetic mechanisms of cytopenias, and we offer insight into cytomorphological aspects, the role of clonal hematopoiesis, and the risk of secondary myeloid malignancies. Subsequently, we expose the major findings and reports on T-cell and B-cell quantitative and functional impairment after CAR-T. Finally, we provide an overview of current recommendations and leading experiences regarding the management of cytopenias and defective B- and T-cell function.

Poor graft function (PGF) is a rare but serious complication of allogeneic hematopoietic cell transplantation (alloHCT). Due to their hematopoietic supporting properties and immune regulatory effects, multipotent mesenchymal stromal cells (MSC) could be considered a good candidate to help to restore bone marrow (BM) niches homeostasis and facilitate hematopoiesis after alloHCT. We prospectively assessed the efficacy and safety of ex-vivo expanded BM-derived MSC from third-party donor in a series of 30 patients with prolonged severe cytopenia and PGF after alloHCT. This multicenter trial was registered at www.clinicaltrials.gov (#NTC00603330). Within 90 days post-MSC infusion, 53% (95% CI, 35 - 71%) of patients improved at least one cytopenia (overall response, OR) and 37% (95% CI, 19 - 54%) achieved a complete hematological response (CR: absolute neutrophil count, ANC >0.5 x 10/L, Hb > 80g/L and platelet count > 20 x 10/L with transfusion independence). Corresponding response rates increased to 67% (95% CI, 50 - 84%) OR and 53% (95% CI, 35 - 71%) CR within 180 days after MSC infusion. A significant decrease in red blood cells and platelets transfusion requirement was observed after MSC (median of 30-days transfusion requirement of 0.5 and 0 from d90-120 post-MSC versus 5 and 6.5 before MSC, respectively, p ≤0.001). An increase in ANC was also noted by day +90 and +180, with 3/5 patients with severe neutropenia having recovered an ANC > 1 x 10/L within the 90-120 days after MSC infusion. Overall survival at 1 year post-MSC was 70% (95% CI, 55.4 - 88.5), with all but one of the patients who achieved CR being alive. A single infusion of third-party MSC appeared to be safe, with the exception of one deep vein thrombotic event possibly related to the intervention. In conclusion, a single i.v. infusion of BM-derived MSC from third party donor seemed to improve hematological function after alloHCT, although spontaneous amelioration cannot be excluded. Comparative studies a

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

BACKGROUND: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity. OBJECTIVE: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants. METHODS: We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3. RESULTS: Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4-CD8-) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate. CONCLUSION: STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome.

[Background] In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity., [Objective] This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants., [Methods] We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3., [Results] Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4−CD8−) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate., [Conclusion] : STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome.

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

BackgroundGaucher disease (GD) diagnosis can be delayed due to non-specific symptoms and lack of awareness, leading to unnecessary procedures and irreversible complications. GAU-PED study aims to assess GD prevalence in a high-risk pediatric population and the presence, if any, of novel clinical or biochemical markers associated with GD.Materials and methodsDBS samples were collected and tested for beta-glucocerebrosidase enzyme activity for 154 patients selected through the algorithm proposed by Di Rocco et al. Patients showing beta-glucocerebrosidase activity below normal values were recalled to confirm the enzyme deficiency with the gold standard essay on cellular homogenate. Patients tested positive at the gold standard analysis were evaluated through GBA1 gene sequencing.Results14 out of 154 patients were diagnosed with GD, with a prevalence of 9.09% (5.06-14.78%, CI 95%). Hepatomegaly, thrombocytopenia, anemia, growth delay/deceleration, elevated serum ferritin, elevated Lyso-Gb1 and chitotriosidase were significantly associated with GD.ConclusionsGD prevalence in a pediatric population at high-risk appeared to be higher compared to high-risk adults. Lyso-Gb1 was associated with GD diagnosis. The algorithm proposed by Di Rocco et al. can potentially improve the diagnostic accuracy of pediatric GD, allowing the prompt start of therapy, aiming to reduce irreversible complications.

We present a case of a healthy 62-year-old woman who developed recurrent seizures preceded by subacute cognitive slowing, ataxia, night sweats, and weight loss. She was found to have cytopenias, multifocal T2/FLAIR hyperintensities on magnetic resonance imaging (MRI), and magnetic susceptibility artifact lesions on susceptibility weighted imaging (SWI). Her symptoms, imaging and laboratory abnormalities all improved with high-doses of steroids and intravenous immunoglobulin (IVIG). But recurred several weeks after completing treatment. Despite extensive work-up, she required multiple hospitalizations and repeat diagnostic studies to arrive at a diagnosis. With an expert discussant in hematology and oncology, we review the differential diagnosis and stepwise approach of unexplained neuro-inflammatory syndromes with cytopenias and systemic symptoms. Our case highlights how time, empiric treatment response, and repeated diagnostic studies refine differential diagnoses and subsequent evaluation. After revealing the diagnosis, we discuss the heterogenous clinical manifestations of this disease process.

Purpose: We described clinical, immunological, and molecular characterization within a cohort of 22 RAG patients focused on the possible correlation between clinical and genetic data. Methods: Immunological and genetic features were investigated by multiparametric flow cytometry and by Sanger or next generation sequencing (NGS) as appropriate. Results: Patients represented a broad spectrum of RAG deficiencies: SCID, OS, LS/AS, and CID. Three novel mutations in RAG1 gene and one in RAG2 were reported. The primary symptom at presentation was infections (81.8%). Infections and autoimmunity occurred together in the majority of cases (63.6%). Fifteen out of 22 (68.2%) patients presented autoimmune or inflammatory manifestations. Five patients experienced severe autoimmune cytopenia refractory to different lines of therapy. Total lymphocytes count was reduced or almost lacking in SCID group and higher in OS patients. B lymphocytes were variably detected in LS/AS and CID groups. Eighteen patients underwent HSCT permitting definitive control of autoimmune/hyperinflammatory manifestations in twelve of them (80%). Conclusion: We reinforce the notion that different clinical phenotype can be found in patients with identical mutations even within the same family. Infections may influence genotype–phenotype correlation and function as trigger for immune dysregulation or autoimmune manifestations. Severe and early autoimmune refractory cytopenia is frequent and could be the first symptom of onset. Prompt recognition of RAG deficiency in patients with early onset of autoimmune/hyperinflammatory manifestations could contribute to the choice of a timely and specific treatment preventing the onset of other complications.

BackgroundHemophagocytic lymphohistiocytosis (HLH) is a life-threatening hematologic disorder resulting from an ineffective and pathologic activation of the immune response system that may mimic common emergency department presentations, including sepsis, acute liver failure, disseminated intravascular coagulation, and flu-like illnesses such as coronavirus disease 2019 (COVID-19).ObjectiveThis narrative review provides a summary of the disease and recommendations for the recognition and diagnostic evaluation of HLH with a focus on the emergency clinician.DiscussionThough the condition is rare, mortality rates are high, ranging from 20% to 80% and increasing with delays in treatment. Importantly, HLH has been recognized as a severe variation of the cytokine storm associated with COVID-19. Common features include a history of infection or malignancy, fever, splenomegaly or hepatomegaly, hyperferritinemia, cytopenias, coagulopathies, abnormal liver enzymes, and hypertriglyceridemia. Using specific features of the history, physical examination, laboratory studies, and tools such as the HScore, HLH-2004/2009, and hyperferritinemia thresholds, the emergency clinician can risk-stratify patients and admit for definitive testing. Once diagnosed, disease specific treatment can be initiated.ConclusionThis review describes the relevant pathophysiology, common presentation findings, and a framework for risk stratification in the emergency department.

BackgroundHemophagocytic lymphohistiocytosis (HLH) is a life-threatening hematologic disorder resulting from an ineffective and pathologic activation of the immune response system that may mimic common emergency department presentations, including sepsis, acute liver failure, disseminated intravascular coagulation, and flu-like illnesses such as coronavirus disease 2019 (COVID-19).ObjectiveThis narrative review provides a summary of the disease and recommendations for the recognition and diagnostic evaluation of HLH with a focus on the emergency clinician.DiscussionThough the condition is rare, mortality rates are high, ranging from 20% to 80% and increasing with delays in treatment. Importantly, HLH has been recognized as a severe variation of the cytokine storm associated with COVID-19. Common features include a history of infection or malignancy, fever, splenomegaly or hepatomegaly, hyperferritinemia, cytopenias, coagulopathies, abnormal liver enzymes, and hypertriglyceridemia. Using specific features of the history, physical examination, laboratory studies, and tools such as the HScore, HLH-2004/2009, and hyperferritinemia thresholds, the emergency clinician can risk-stratify patients and admit for definitive testing. Once diagnosed, disease specific treatment can be initiated.ConclusionThis review describes the relevant pathophysiology, common presentation findings, and a framework for risk stratification in the emergency department.

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of cancers and inflammation-related diseases. This phenomenon becomes common in persons aged ≥80 years, in whom the implications of CHIP are not well defined. We performed a mutational screening in 1794 persons aged ≥80 years and investigated the relationships between CHIP and associated pathologies. Mutations were observed in one-third of persons aged ≥80 years and were associated with reduced survival. Mutations in JAK2 and splicing genes, multiple mutations (DNMT3A, TET2, and ASXL1 with additional genetic lesions), and variant allele frequency ≥0.096 had positive predictive value for myeloid neoplasms. Combining mutation profiles with abnormalities in red blood cell indices improved the ability of myeloid neoplasm prediction. On this basis, we defined a predictive model that identifies 3 risk groups with different probabilities of developing myeloid neoplasms. Mutations in DNMT3A, TET2, ASXL1, or JAK2 were associated with coronary heart disease and rheumatoid arthritis. Cytopenia was common in persons aged ≥80 years, with the underlying cause remaining unexplained in 30% of cases. Among individuals with unexplained cytopenia, the presence of highly specific mutation patterns was associated with myelodysplastic-like phenotype and a probability of survival comparable to that of myeloid neoplasms. Accordingly, 7.5% of subjects aged ≥80 years with cytopenia had presumptive evidence of myeloid neoplasm. In summary, specific mutational patterns define different risk of developing myeloid neoplasms vs inflammatory-associated diseases in persons aged ≥80 years. In individuals with unexplained cytopenia, mutational status may identify those subjects with presumptive evidence of myeloid neoplasms.

This retrospective study assessed the effectiveness of eltrombopag (EPAG), a thrombopoietin receptor agonist, in the treatment of poor graft function (PGF) following an allogeneic haemopoietic stem cell transplantation (HSCT). Complete response was defined as normalization of blood counts, whereas partial response was defined as transfusion independence. A total of 48 patients with full donor chimerism after HSCT, received EPAG for a median of 120 days (range 10–591). Patients with uni- bi- or tri-lineage cytopenia started treatment at a median of 95 days (range 17–877) after HSCT. The overall response rate was 75%: 24 patients had a complete response and 12 had a partial response. Positive predictors of response were an HLA-matched donor, a CD34+ dose at transplant > 4 × 106/kg, and starting EPAG treatment at least 90 days after HSCT. Patients with more than one positive predictor had a response rate of 92% for the overall patient cohort and 94% for patients with tri-lineage cytopenia. One-year survival was 89% for complete responders, 60% for partial responders and 20% for non-responders (p = 0.0004). EPAG improves peripheral blood counts in patients with poor graft function following HSCT. Response to EPAG can be predicted and has a significant impact on survival.

Coronavirus disease 2019 (COVID-19) has been categorized as evolving in overlapping phases. First, there is a viral phase that may well be asymptomatic or mild in the majority, perhaps 80% of patients. The pathophysiological mechanisms resulting in minimal disease in this initial phase are not well known. In the remaining 20% of cases, the disease may become severe and/or critical. In most patients of this latter group, there is a phase characterized by the hyperresponsiveness of the immune system. A third phase corresponds to a state of hypercoagulability. Finally, in the fourth stage organ injury and failure occur. Appearance of autoinflammatory/autoimmune phenomena in patients with COVID-19 calls attention for the development of new strategies for the management of life-threatening conditions in critically ill patients. Antiphospholipid syndrome, autoimmune cytopenia, Guillain-Barré syndrome and Kawasaki disease have each been reported in patients with COVID-19. Here we present a scoping review of the relevant immunological findings in COVID-19 as well as the current reports about autoinflammatory/autoimmune conditions associated with the disease. These observations have crucial therapeutic implications since immunomodulatory drugs are at present the most likely best candidates for COVID-19 therapy. Clinicians should be aware of these conditions in patients with COVID-19, and these observations should be considered in the current development of vaccines.

Dasatinib has shown superiority over imatinib in achieving molecular responses (MRs) in chronic phase chronic myeloid leukemia but with a different toxicity profile, which may impact its overall benefit. Reported toxicities include pleural effusions and pulmonary hypertension, and although the incidence of these events is well described, response to therapy and impact of dose modifications on toxicity has not been comprehensively characterized in a real-world setting. We retrospectively reviewed the incidence of dasatinib adverse events in 212 chronic phase chronic myeloid leukemia patients at 17 Australian institutions. Adverse events were reported in 116 patients (55%), most commonly pleural effusions (53 patients, 25%), which was the predominant cause of permanent drug cessation. Age and dose were risk factors for pleural effusion (P < .01 and .047, respectively). Recurrence rates were higher in those who remained on 100 mg compared with those who dose reduced (P = .041); however, recurrence still occurred at 50 mg. Patients who developed pleural effusions were more likely to have achieved MR4.5 after 6 months of dasatinib than those without effusions (P = .008). Pulmonary hypertension occurred in 5% of patients, frequently in association with pleural effusion, and was reversible upon dasatinib cessation in 6 of 7 patients. Dose reductions and temporary cessations had minimal impact on MR rates. Our observations suggest that by using the lowest effective dose in older patients to minimize the effusion risk, dose modification for cytopenias, and care with concomitant antiplatelet therapy, the necessity for permanent dasatinib cessation due to toxicity is likely to be minimal in immunologically competent patients.

Dasatinib has shown superiority over imatinib in achieving molecular responses (MRs) in chronic phase chronic myeloid leukemia but with a different toxicity profile, which may impact its overall benefit. Reported toxicities include pleural effusions and pulmonary hypertension, and although the incidence of these events is well described, response to therapy and impact of dose modifications on toxicity has not been comprehensively characterized in a real-world setting. We retrospectively reviewed the incidence of dasatinib adverse events in 212 chronic phase chronic myeloid leukemia patients at 17 Australian institutions. Adverse events were reported in 116 patients (55%), most commonly pleural effusions (53 patients, 25%), which was the predominant cause of permanent drug cessation. Age and dose were risk factors for pleural effusion (P < .01 and .047, respectively). Recurrence rates were higher in those who remained on 100 mg compared with those who dose reduced (P = .041); however, recurrence still occurred at 50 mg. Patients who developed pleural effusions were more likely to have achieved MR4.5 after 6 months of dasatinib than those without effusions (P = .008). Pulmonary hypertension occurred in 5% of patients, frequently in association with pleural effusion, and was reversible upon dasatinib cessation in 6 of 7 patients. Dose reductions and temporary cessations had minimal impact on MR rates. Our observations suggest that by using the lowest effective dose in older patients to minimize the effusion risk, dose modification for cytopenias, and care with concomitant antiplatelet therapy, the necessity for permanent dasatinib cessation due to toxicity is likely to be minimal in immunologically competent patients.

Coronavirus disease 2019 (COVID-19) has been categorized as evolving in overlapping phases. First, there is a viral phase that may well be asymptomatic or mild in the majority, perhaps 80% of patients. The pathophysiological mechanisms resulting in minimal disease in this initial phase are not well known. In the remaining 20% of cases, the disease may become severe and/or critical. In most patients of this latter group, there is a phase characterized by the hyperresponsiveness of the immune system. A third phase corresponds to a state of hypercoagulability. Finally, in the fourth stage organ injury and failure occur. Appearance of autoinflammatory/autoimmune phenomena in patients with COVID-19 calls attention for the development of new strategies for the management of life-threatening conditions in critically ill patients. Antiphospholipid syndrome, autoimmune cytopenia, Guillain-Barré syndrome and Kawasaki disease have each been reported in patients with COVID-19. Here we present a scoping review of the relevant immunological findings in COVID-19 as well as the current reports about autoinflammatory/autoimmune conditions associated with the disease. These observations have crucial therapeutic implications since immunomodulatory drugs are at present the most likely best candidates for COVID-19 therapy. Clinicians should be aware of these conditions in patients with COVID-19, and these observations should be considered in the current development of vaccines.

Background: Rituximab (RTX; anti-CD20 mAb) is a treatment option in children with refractory immune thrombocytopenia, autoimmune hemolytic anemia (AHA), and Evans syndrome (ES). Prevalence and clinical course of RTX-induced hypogammaglobulinemia in these patients are poorly known. Objective: To evaluate the prevalence and risk factors for persistent hypogammaglobulinemia (PH) after RTX use. Methods: Clinical and immunologic data from children treated with RTX for immune thrombocytopenia, AHA, and ES were collected from 16 Italian centers and 1 UK center at pre-RTX time point (0), +6 months, and yearly, up to 4 years post-RTX. Patients with previously diagnosed malignancy or primary immune deficiency (PID) were excluded. Results: We analyzed 53 children treated with RTX for immune thrombocytopenia (n = 36), AHA (n = 13), and ES (n = 4). Median follow-up was 30 months (range, 12-48). Thirty-two percent of patients (17 of 53) experienced PH, defined as IgG levels less than 2 SD for age at last follow-up (>12 months after RTX). Significantly delayed B-cell recovery was observed in children experiencing PH (hazard ratio, 0.55; P <.05), and 6 of 17 (35%) patients had unresolved B-cell lymphopenia at last follow-up. PH was associated with IgA and IgM deficiency, younger age at RTX use (51 vs 116 months; P <.01), a diagnosis of AHA/ES, and better response to RTX. Nine patients with PH (9 of 17 [53%]) were eventually diagnosed with a PID. Conclusions: Post-RTX PH is a frequent condition in children with autoimmune cytopenia; a sizable proportion of patients with post-RTX PH were eventually diagnosed with a PID. In-depth investigation for PID is therefore recommended in these patients.

Steven Johnson Syndrome (SJS) and toxic epidermolysis necrosis (TEN) are rare dermatological emergencies causing a painful mucocutaneous rash which bears a mortality rate of approximately 5%. This condition can be associated with systemic symptoms of fever, lymphadenopathy, hepatitis, cytopenias and cholestasis due to vanishing bile duct syndrome. Furthermore, epithelium from the respiratory tract and gastrointestinal lesions can also occur but cerebellitis is not known to co-exist with this disorder. We present a case of a 10 year old boy with SJS/TEN associated with cerebellitis. The patient presented with a 6 day history of a morbilliform desquamating rash affecting 25% of his total skin body surface area, fever, erosions of the oral, ocular and urethral mucosa and encephalopathy. The suspected aetiology was likely secondary to amoxicillin and a possible infection. Laboratory investigations identified an acute hepatitis, pancytopaenia with negative herpes simplex virus and mycoplasma mucosal swabs. Histology displayed lichenoid inflammatory changes with basal vacuolar degeneration, lymphocytic cell exocytosis and apoptosis consistent with SJS. Magnetic resonance imaging of the brain showed diffuse low signalling involving the brain stem and cerebellum suggestive of cerebellitis. We present findings from a literature review of evidence reporting cases of cerebellitis or neurological inflammation occurring alongside SJS/TEN.

Background: Prior to the introduction of combination antiretroviral therapy (cART), cytopenias were common in people with human immunodeficiency virus (PWH), but it is unknown if well-controlled HIV infection is a risk factor for cytopenia. In this study we aimed to determine if HIV infection is an independent risk factor for anemia, neutropenia, lymphocytopenia, and thrombocytopenia. Methods: PWH with undetectable viral replication and absence of chronic hepatitis infection (n = 796) were recruited from the Copenhagen Comorbidity in HIV Infection (COCOMO) study and matched uninfected controls from the Copenhagen General Population Study (n = 2388). Hematology was analyzed in venous blood samples. Logistic regression analyses adjusted for age, sex, ethnicity, smoking status, alcohol, and high-sensitivity C-reactive protein were performed to determine possible associations between HIV and cytopenias. Results: PWH had a higher prevalence of anemia (6.9% vs 3.4%, P <. 001), neutropenia (1.3% vs 0.2%, P <. 001), and thrombocytopenia (5.5% vs 2.7%, P <. 001) compared with uninfected controls. HIV was independently associated with anemia-Adjusted odds ratio (aOR) of 2.0 (95% confidence interval [CI], 1.4-3.0); neutropenia aOR, 6.3 (95% CI, 2.0-19.6); and thrombocytopenia aOR, 2.7 (95% CI, 1.8-4.2). No association was found between HIV and lymphocytopenia. Conclusions: Cytopenia is rare in people with well-controlled HIV, but HIV remains a risk factor for anemia, neutropenia, and thrombocytopenia and requires ongoing attention and monitoring.

Steven Johnson Syndrome (SJS) and toxic epidermolysis necrosis (TEN) are rare dermatological emergencies causing a painful mucocutaneous rash which bears a mortality rate of approximately 5%. This condition can be associated with systemic symptoms of fever, lymphadenopathy, hepatitis, cytopenias and cholestasis due to vanishing bile duct syndrome. Furthermore, epithelium from the respiratory tract and gastrointestinal lesions can also occur but cerebellitis is not known to co-exist with this disorder. We present a case of a 10 year old boy with SJS/TEN associated with cerebellitis. The patient presented with a 6 day history of a morbilliform desquamating rash affecting 25% of his total skin body surface area, fever, erosions of the oral, ocular and urethral mucosa and encephalopathy. The suspected aetiology was likely secondary to amoxicillin and a possible infection. Laboratory investigations identified an acute hepatitis, pancytopaenia with negative herpes simplex virus and mycoplasma mucosal swabs. Histology displayed lichenoid inflammatory changes with basal vacuolar degeneration, lymphocytic cell exocytosis and apoptosis consistent with SJS. Magnetic resonance imaging of the brain showed diffuse low signalling involving the brain stem and cerebellum suggestive of cerebellitis. We present findings from a literature review of evidence reporting cases of cerebellitis or neurological inflammation occurring alongside SJS/TEN.

Background: Prior to the introduction of combination antiretroviral therapy (cART), cytopenias were common in people with human immunodeficiency virus (PWH), but it is unknown if well-controlled HIV infection is a risk factor for cytopenia. In this study we aimed to determine if HIV infection is an independent risk factor for anemia, neutropenia, lymphocytopenia, and thrombocytopenia. Methods: PWH with undetectable viral replication and absence of chronic hepatitis infection (n = 796) were recruited from the Copenhagen Comorbidity in HIV Infection (COCOMO) study and matched uninfected controls from the Copenhagen General Population Study (n = 2388). Hematology was analyzed in venous blood samples. Logistic regression analyses adjusted for age, sex, ethnicity, smoking status, alcohol, and high-sensitivity C-reactive protein were performed to determine possible associations between HIV and cytopenias. Results: PWH had a higher prevalence of anemia (6.9% vs 3.4%, P <. 001), neutropenia (1.3% vs 0.2%, P <. 001), and thrombocytopenia (5.5% vs 2.7%, P <. 001) compared with uninfected controls. HIV was independently associated with anemia-Adjusted odds ratio (aOR) of 2.0 (95% confidence interval [CI], 1.4-3.0); neutropenia aOR, 6.3 (95% CI, 2.0-19.6); and thrombocytopenia aOR, 2.7 (95% CI, 1.8-4.2). No association was found between HIV and lymphocytopenia. Conclusions: Cytopenia is rare in people with well-controlled HIV, but HIV remains a risk factor for anemia, neutropenia, and thrombocytopenia and requires ongoing attention and monitoring.

Background: Predominantly antibody deficiencies (PADs) are the most common type of primary immunodeficiency in adults. PADs frequently pass undetected leading to delayed diagnosis, delayed treatment, and the potential for end-organ damage including bronchiectasis. In addition, PADs are frequently accompanied by comorbid autoimmune disease, and an increased risk of malignancy. Objective(s): To characterize the diagnostic and clinical features of adult PAD patients in Victoria, Australia. Method(s): We identified adult patients receiving, or having previously received immunoglobulin replacement therapy for a PAD at four hospitals in metropolitan Melbourne, and retrospectively characterized their clinical and diagnostic features. Result(s): 179 patients from The Royal Melbourne, Alfred and Austin Hospitals, and Monash Medical Centre were included in the study with a median age of 49.7 years (range: 16-87 years), of whom 98 (54.7%) were female. The majority of patients (116; 64.8%) met diagnostic criteria for common variable immunodeficiency (CVID), and 21 (11.7%) were diagnosed with X-linked agammaglobulinemia (XLA). Unclassified hypogammaglobulinemia (HGG) was described in 22 patients (12.3%), IgG subclass deficiency (IGSCD) in 12 (6.7%), and specific antibody deficiency (SpAD) in 4 individuals (2.2%). The remaining four patients had a diagnosis of Good syndrome (thymoma with immunodeficiency). There was no significant difference between the age at diagnosis of the disorders, with the exception of XLA, with a median age at diagnosis of less than 1 year. The median age of reported symptom onset was 20 years for those with a diagnosis of CVID, with a median age at diagnosis of 35 years. CVID patients experienced significantly more non-infectious complications, such as autoimmune cytopenias and lymphoproliferative disease, than the other antibody deficiency disorders. The presence of non-infectious complications was associated with significantly reduced survival in the c

Background: Predominantly antibody deficiencies (PADs) are the most common type of primary immunodeficiency in adults. PADs frequently pass undetected leading to delayed diagnosis, delayed treatment, and the potential for end-organ damage including bronchiectasis. In addition, PADs are frequently accompanied by comorbid autoimmune disease, and an increased risk of malignancy. Objective(s): To characterize the diagnostic and clinical features of adult PAD patients in Victoria, Australia. Method(s): We identified adult patients receiving, or having previously received immunoglobulin replacement therapy for a PAD at four hospitals in metropolitan Melbourne, and retrospectively characterized their clinical and diagnostic features. Result(s): 179 patients from The Royal Melbourne, Alfred and Austin Hospitals, and Monash Medical Centre were included in the study with a median age of 49.7 years (range: 16-87 years), of whom 98 (54.7%) were female. The majority of patients (116; 64.8%) met diagnostic criteria for common variable immunodeficiency (CVID), and 21 (11.7%) were diagnosed with X-linked agammaglobulinemia (XLA). Unclassified hypogammaglobulinemia (HGG) was described in 22 patients (12.3%), IgG subclass deficiency (IGSCD) in 12 (6.7%), and specific antibody deficiency (SpAD) in 4 individuals (2.2%). The remaining four patients had a diagnosis of Good syndrome (thymoma with immunodeficiency). There was no significant difference between the age at diagnosis of the disorders, with the exception of XLA, with a median age at diagnosis of less than 1 year. The median age of reported symptom onset was 20 years for those with a diagnosis of CVID, with a median age at diagnosis of 35 years. CVID patients experienced significantly more non-infectious complications, such as autoimmune cytopenias and lymphoproliferative disease, than the other antibody deficiency disorders. The presence of non-infectious complications was associated with significantly reduced survival in the c

Obinutuzumab (G) is a glycoengineered type II anti-CD20 monoclonal antibody with promising activity and manageable toxicity when combined with chemotherapy in relapsed iNHL. GALLIUM (NCT01332968) is an open-label, randomised Phase 3 study comparing the efficacy and safety of rituximab (R) or G with chemotherapy followed by maintenance as first-line treatment in iNHL. Patients (pts) were aged >=18 years with previously untreated follicular lymphoma (FL) (grades 1-3a) or chemotherapy-nave marginal zone lymphoma (MZL), stage III/IV disease or stage II with tumour diameter >=7 cm, ECOG PS 0-2, and requiring treatment according to GELF criteria. CHOP, CVP, or bendamustine (B) were allocated according to centre (FL) or pt (MZL). Pts were randomised 1:1 and stratified by chemotherapy, FLIPI/IPI group, and geographic region to receive R 375 mg/m2 on D1 of each cycle or G 1000 mg on D1, 8, 15 of Cycle 1 and D1 of subsequent cycles, for either 8 x 21-day cycles (CHOP, CVP) or 6 x 28-day cycles (B). Pts with a CR or PR at the end of induction (EOI) received R or G every 2 months for 2 years or until disease progression. The primary endpoint was investigator-assessed PFS in FL pts. The current data are from an interim efficacy analysis done when a planned 67% of 370 PFS events had occurred (cut-off date: Jan 31, 2016) after which the study was unblinded on IDMC recommendation. Results are reported for 1202 FL pts (R-chemo, 601; G-chemo, 601); median age 59 years, 53.2% female. Treatment arms were well balanced by disease stage (Ann Arbor: I, 1.5%; II, 7.1%; III, 34.9%; IV, 56.5%) and prognostic factors (FLIPI: 0 + 1, 21.0%; 2, 37.2%; >=3, 41.8%; FLIPI-2: 0, 9.1%; 1 + 2, 50.3%; >=3, 40.6%). 686 patients (57.1%) received B, 33.1% CHOP, and 9.8% CVP. CR and ORR at EOI were similar for the two arms. There was a 34% reduction in the risk of progression or death (HR 0.66; 95% CI, 0.51-0.85; p = 0.001; median follow-up 34.5 months, range 0-54.5). Although the median PFS has not been r

Obinutuzumab (G) is a glycoengineered type II anti-CD20 monoclonal antibody with promising activity and manageable toxicity when combined with chemotherapy in relapsed iNHL. GALLIUM (NCT01332968) is an open-label, randomised Phase 3 study comparing the efficacy and safety of rituximab (R) or G with chemotherapy followed by maintenance as first-line treatment in iNHL. Patients (pts) were aged >=18 years with previously untreated follicular lymphoma (FL) (grades 1-3a) or chemotherapy-nave marginal zone lymphoma (MZL), stage III/IV disease or stage II with tumour diameter >=7 cm, ECOG PS 0-2, and requiring treatment according to GELF criteria. CHOP, CVP, or bendamustine (B) were allocated according to centre (FL) or pt (MZL). Pts were randomised 1:1 and stratified by chemotherapy, FLIPI/IPI group, and geographic region to receive R 375 mg/m2 on D1 of each cycle or G 1000 mg on D1, 8, 15 of Cycle 1 and D1 of subsequent cycles, for either 8 x 21-day cycles (CHOP, CVP) or 6 x 28-day cycles (B). Pts with a CR or PR at the end of induction (EOI) received R or G every 2 months for 2 years or until disease progression. The primary endpoint was investigator-assessed PFS in FL pts. The current data are from an interim efficacy analysis done when a planned 67% of 370 PFS events had occurred (cut-off date: Jan 31, 2016) after which the study was unblinded on IDMC recommendation. Results are reported for 1202 FL pts (R-chemo, 601; G-chemo, 601); median age 59 years, 53.2% female. Treatment arms were well balanced by disease stage (Ann Arbor: I, 1.5%; II, 7.1%; III, 34.9%; IV, 56.5%) and prognostic factors (FLIPI: 0 + 1, 21.0%; 2, 37.2%; >=3, 41.8%; FLIPI-2: 0, 9.1%; 1 + 2, 50.3%; >=3, 40.6%). 686 patients (57.1%) received B, 33.1% CHOP, and 9.8% CVP. CR and ORR at EOI were similar for the two arms. There was a 34% reduction in the risk of progression or death (HR 0.66; 95% CI, 0.51-0.85; p = 0.001; median follow-up 34.5 months, range 0-54.5). Although the median PFS has not been r

Background: Conventional therapy of autoimmune hepatitis (AIH) is with corticosteroids with or without azathioprine. However, 20% of patients do not respond or are intolerant to standard therapy. Thus, we evaluated the efficacy and safety of mycophenolate mofetil (MMF) in AIH patients who had failed or were intolerant to corticosteroids with or without azathioprine. Method(s): A retrospective study was performed of AIH patients who received MMF alone or in combination with prednisolone after failure or intolerance of standard therapy. Patients were recruited from 16 liver clinics across Australia via the ALA Clinical Research Network. Records were reviewed for baseline demographics and liver disease characteristics, initial therapy, indications for MMF initiation, treatment outcome and complications. Result(s): A total of 96 patients (mean age 45.3 yrs, females 86.5%, Caucasian 53% and cirrhosis 19.8%) received treatment with MMF for AIH across the 16 centres including 95 in combination with corticosteroids. The majority (73%) had received prior combination therapy with corticosteroids plus azathioprine/6-mercaptopurine. The indication for MMF was non-response in 43% and intolerance to standard therapy in 53%. The median starting and maximal doses of MMF received was 1 g/d and 2 g/d, respectively; the median treatment duration was 31.9 months. Overall, 44 (45.9%) patients achieved biochemical remission on MMF after a median treatment duration of 11 weeks, 8 (18%) of whom relapsed during follow up. Of the 40 patients treated for non-response, 17 (42.5%) achieved biochemical remission after a median of 12 weeks, while 8 (20%) had an incomplete response and 3 (7.5%) had treatment failure. Of the 49 patients receiving MMF for intolerance/toxicity, 27 (55%) achieved remission, with 4 (8%) having an incomplete response and 1 (2%) treatment failure. Eight patients required dose-reduction, and 16 discontinued MMF mainly due to lack of efficacy (n = 6) or intolerance (n = 6)

Background Conventional therapy of autoimmune hepatitis (AIH) is with corticosteroids with or without azathioprine. However 20% of patients do not respond or are intolerant to standard therapy. Thus, we evaluated the efficacy and safety of mycophenolate mofetil (MMF) in AIH patients who had failed or were intolerant to corticosteroids with or without azathioprine. Methods A retrospective study was performed of AIH patients who received MMF alone or in combination with prednisolone after failure or intolerance of standard therapy. Patients were recruited from 16 liver clinics across Australia via the ALA Clinical Research Network. Records were reviewed for baseline demographics and liver disease characteristics, initial therapy, indications for MMF initiation, treatment outcome and complications. Results A total of 96 patients (mean age 45.3 yrs, females 86.5%, Caucasian 53%, cirrhosis 19.8%) received treatment with MMF for AIH across the 16 centres including 95 in combination with corticosteroids. The majority (73%) had received prior combination therapy with corticosteroids plus azathioprine/6-mercaptopurine. The indication for MMF was non-response in 43% and intolerance to standard therapy in 53%. The median starting and maximal doses of MMF received was 1gm/d and 2gm/d respectively; the median treatment duration was 31.9 months. Overall, 44 (45.9%) patients achieved biochemical remission on MMF after a median treatment duration of 11 weeks, 8 (18%) of whom relapsed during follow up. Of the 40 patients treated for non-response, 17 (42.5%) achieved biochemical remission after a median of 12 weeks, while 8 (20%) had an incomplete response and 3 (7.5%) had treatment failure. Of the 49 patients receiving MMF for intolerance/toxicity, 27 (55%) achieved remission, with 4 (8%) having an incomplete response and 1 (2%) treatment failure. 8 patients required dose-reduction and 16 discontinued MMF mainly due to lack of efficacy (n=6) or intolerance (n=6). Serious adverse eve

Background: Conventional therapy of autoimmune hepatitis (AIH) is with corticosteroids with or without azathioprine. However, 20% of patients do not respond or are intolerant to standard therapy. Thus, we evaluated the efficacy and safety of mycophenolate mofetil (MMF) in AIH patients who had failed or were intolerant to corticosteroids with or without azathioprine. Method(s): A retrospective study was performed of AIH patients who received MMF alone or in combination with prednisolone after failure or intolerance of standard therapy. Patients were recruited from 16 liver clinics across Australia via the ALA Clinical Research Network. Records were reviewed for baseline demographics and liver disease characteristics, initial therapy, indications for MMF initiation, treatment outcome and complications. Result(s): A total of 96 patients (mean age 45.3 yrs, females 86.5%, Caucasian 53% and cirrhosis 19.8%) received treatment with MMF for AIH across the 16 centres including 95 in combination with corticosteroids. The majority (73%) had received prior combination therapy with corticosteroids plus azathioprine/6-mercaptopurine. The indication for MMF was non-response in 43% and intolerance to standard therapy in 53%. The median starting and maximal doses of MMF received was 1 g/d and 2 g/d, respectively; the median treatment duration was 31.9 months. Overall, 44 (45.9%) patients achieved biochemical remission on MMF after a median treatment duration of 11 weeks, 8 (18%) of whom relapsed during follow up. Of the 40 patients treated for non-response, 17 (42.5%) achieved biochemical remission after a median of 12 weeks, while 8 (20%) had an incomplete response and 3 (7.5%) had treatment failure. Of the 49 patients receiving MMF for intolerance/toxicity, 27 (55%) achieved remission, with 4 (8%) having an incomplete response and 1 (2%) treatment failure. Eight patients required dose-reduction, and 16 discontinued MMF mainly due to lack of efficacy (n = 6) or intolerance (n = 6)

Background Conventional therapy of autoimmune hepatitis (AIH) is with corticosteroids with or without azathioprine. However 20% of patients do not respond or are intolerant to standard therapy. Thus, we evaluated the efficacy and safety of mycophenolate mofetil (MMF) in AIH patients who had failed or were intolerant to corticosteroids with or without azathioprine. Methods A retrospective study was performed of AIH patients who received MMF alone or in combination with prednisolone after failure or intolerance of standard therapy. Patients were recruited from 16 liver clinics across Australia via the ALA Clinical Research Network. Records were reviewed for baseline demographics and liver disease characteristics, initial therapy, indications for MMF initiation, treatment outcome and complications. Results A total of 96 patients (mean age 45.3 yrs, females 86.5%, Caucasian 53%, cirrhosis 19.8%) received treatment with MMF for AIH across the 16 centres including 95 in combination with corticosteroids. The majority (73%) had received prior combination therapy with corticosteroids plus azathioprine/6-mercaptopurine. The indication for MMF was non-response in 43% and intolerance to standard therapy in 53%. The median starting and maximal doses of MMF received was 1gm/d and 2gm/d respectively; the median treatment duration was 31.9 months. Overall, 44 (45.9%) patients achieved biochemical remission on MMF after a median treatment duration of 11 weeks, 8 (18%) of whom relapsed during follow up. Of the 40 patients treated for non-response, 17 (42.5%) achieved biochemical remission after a median of 12 weeks, while 8 (20%) had an incomplete response and 3 (7.5%) had treatment failure. Of the 49 patients receiving MMF for intolerance/toxicity, 27 (55%) achieved remission, with 4 (8%) having an incomplete response and 1 (2%) treatment failure. 8 patients required dose-reduction and 16 discontinued MMF mainly due to lack of efficacy (n=6) or intolerance (n=6). Serious adverse eve

The myelodysplastic syndromes (MDS) are a group of clonal haematopoietic stem cell diseases characterised by cytopenia(s), dysplasia in one or more myeloid cell lineages, ineffective haematopoiesis and an increased risk of developing acute myeloid leukaemia. In low-to-intermediate risk MDS the bone marrow is composed of a mixture of defective and normal haematopoietic stem and progenitor cells. It has been postulated that the presence of cytokines such as IL-17, TNFalpha and IFNgamma in the bone marrow environment of MDS patients is pro-inflammatory that in turn suppresses haematopoiesis from normal stem cells whilst promoting the survival of abnormal clones culminating in the evolution of the disease. MDS patients exhibit a varying degree and number of cytopenias that often require blood transfusions. Some studies have suggested an adverse impact of transfusion dependence and iron overload on survival in low-to-intermediate risk MDS necessitating iron chelation therapy (ICT). A recently published meta-analysis of 8 observational studies strongly supports the notion of improved survival as a consequence of ICT in patients suffering from transfusional iron overload. We have observed improvement in haematopoietic parameters in a proportion of patients with low-to-intermediate risk MDS treated with the oral iron chelator deferasirox (DFX). Our experimental results suggest that the haematopoietic response following treatment is likely to be a consequence of two distinct functions of DFX. Firstly, DFX inhibits NF-kappaB activity resulting in dampened inflammation in the bone marrow milieu. Secondly, iron chelation leads to mitochondrial dysfunction resulting in apoptosis of malignant clones whilst sparing normal haematopoietic stem cells. Our study provides for the first time a mechanistic basis for improved haematopoiesis in MDS patients treated with ICT.

Teaching and research clinic name of Sultan Suleyman, Turkey. Blood consists of plasma and liquid portion disposed therein formed elements (red cells, white cells, platelets). Because of the volume of blood formed elements of the share falls to 40-45% in the plasma fraction of 55-60%. Cytopenia - a pathological condition which is characterized by decrease in any one of the elements of circulating blood (white blood cells, platelets and red blood cells), pancytopenia - a condition characterized by a decrease in the composition of all the elements and bitsitopeniya - a reduction of two elements of the blood that form its membership. Hypoplasia causes status data - reducing the amount of tissue or cellular elements of the organ or aplasia - the termination or breach of regeneration formed elements.When pancytopenia and bitsitopenii suffer lymphatic, immune and hematopoietic systems. Pathological processes among agencies undergo lymph nodes, bone marrow, spleen and lymphoid tissue. Often it is accompanied by hyperplasia, dysplasia, necrosis of tissue and organ degeneration.The purpose of this study was to evaluate the clinical and hematological parameters in children with bitsitopeniey.The study was conducted from January to March 2012 in teaching and research hospital named after Sultan Suleiman. To accomplish our tasks in the study included 1272 patients in 58 (4.56%) which was identified bitsitopeniya. The age of patients ranged from 2 to 7 years. The boys were 30 (51.7%), 28 girls (48.3%).All patients underwent detailed investigations of hemogram, smear of peripheral blood, biochemical blood tests (urea, creatinine, ALT, AST, LDH, electrolytes sulfur kollesterol, triglycerides, etc.). These studies combined with other laboratory and instrumental methods of assessment of patients. Patients with bitsitopeniey with unknown etiology and detection in peripheral blood smear malignant cells or suspicious for malignancy held aspiration of cerebrospinal fluid.When a patient, Кровь состоит из жидкой части плазмы и расположенных в ней форменных элементов (эритроцитов, лейкоцитов, тромбоцитов). Из объема крови на долю форменных элементов приходится 40-45%, на долю плазмы - 55-60%. Цитопения - это патологическое состояние, для которого характерно снижение какого-либо одного из элементов циркулирующей крови (лейкоциты, тромбоциты и эритроциты), панцитопения – это состояние, характеризующейся снижением состава всех элементов, а бицитопения – это снижение двух элементов крови, которые формируют ее состав. Обуславливаются данные состояния гипоплазией – уменьшением количества ткани либо клеточных элементов органа, либо аплазией – прекращением либо нарушением регенерации форменных элементов. При панцитопении и бицитопении страдают лимфатическая, иммунная и кроветворная системы. Патологическому процессу среди органов подвергаются лимфоузлы, костный мозг, селезенка и лимфоидные ткани. Зачастую он сопровождается гиперплазией, дисплазией, некрозом тканей и органов, дегенерацией. Целью настоящего исследования явилось изучение клинических и гематологических показателей у детей с бицитопенией.Исследование проводилось в период с января по март 2012 года в учебно-исследовательской клинике имени Султана Сулеймана. Для выполнения поставленной нами задачи в исследование было включено 1272 больных у 58 (4,56%) которых была выявлена бицитопения. Возраст больных колебался от 2 до 7 лет. Мальчиков было 30 (51,7%), девочек - 28 (48,3%).Всем больным проводились детальные исследования гемограммы, исследование мазка периферической крови, биохимические анализы крови (мочевина, креатинин, ALT, AST, LDH, электролиты серы, холестерол, триглицериды и тд.). Данные исследования сочетались с применением других лабораторных и инструментальных методов оценки состояния больных. Больным с бицитопенией невыясненной этиологии и при обнаружении в мазке периферической крови злокачественных клеток или клеток с подозрением на малигнизацию проводилась аспирация спинномозго, Кров складається з рідкої частини плазми і розташованих в ній формених елементів (еритроцитів, лейкоцитів, тромбоцитів). З обсягу крові на частку формених елементів доводиться 40-45%, на частку плазми 55-60%. Цитопения - це патологічний стан, для якого характерне зниження якого-небудь одного з елементів циркулюючої крові (лейкоцити, тромбоцити і еритроцити), панцитопенія - це стан, що характеризується зниженням складу всіх елементів, а біцітопенія - це зниження двох елементів крові, які формують її складу . Обумовлюються дані стану гіпоплазією - зменшенням кількості тканини або клітинних елементів органу, або аплазією - припиненням або порушенням регенерації формених елементів. При панцитопенії і біцітопеніі страждають лімфатична, імунна і кровотворна системи. Патологічному процесу серед органів піддаються лімфовузли, кістковий мозок, селезінка і лімфоїдні тканини. Найчастіше він супроводжується гіперплазією, дисплазією, некрозом тканин і органів, дегенерацією. Метою цього дослідження було вивчення клінічних та гематологічних показників у дітей з біцітопеніей.Дослідження проводилося в період з січня по березень 2012 року в навчально-дослідної клініці імені Султана Сулеймана. Для виконання поставленої нами задачі в дослідження було включено тисячі двісті сімдесят два хворих у 58 (4,56%) яких була виявлена біцітопенія. Вік хворих коливався від 2 до 7 років. Хлопчиків було 30 (51,7%), дівчаток 28 (48,3%).Всім хворим проводилися детальні дослідження гемограми, дослідження мазка периферичної крові, біохімічні аналізи крові (сечовина, креатинін, ALT, AST, LDH, електроліти сірки, коллестерол, тригліцериди і тд.). Дані дослідження поєднувалися з застосуванням інших лабораторних та інструментальних методів оцінки стану хворих. Хворим з біцітопеніей з нез'ясованою етіологією і при виявленні в мазку периферичної крові злоякісних клітин або клітин з підозрою на малигнизацию проводилася аспірація спинномозкової рідини.При надходженні хворих у клініку основними скаргами були: у 2

The myelodysplastic syndromes (MDS) are a group of clonal haematopoietic stem cell diseases characterised by cytopenia(s), dysplasia in one or more myeloid cell lineages, ineffective haematopoiesis and an increased risk of developing acute myeloid leukaemia. In low-to-intermediate risk MDS the bone marrow is composed of a mixture of defective and normal haematopoietic stem and progenitor cells. It has been postulated that the presence of cytokines such as IL-17, TNFalpha and IFNgamma in the bone marrow environment of MDS patients is pro-inflammatory that in turn suppresses haematopoiesis from normal stem cells whilst promoting the survival of abnormal clones culminating in the evolution of the disease. MDS patients exhibit a varying degree and number of cytopenias that often require blood transfusions. Some studies have suggested an adverse impact of transfusion dependence and iron overload on survival in low-to-intermediate risk MDS necessitating iron chelation therapy (ICT). A recently published meta-analysis of 8 observational studies strongly supports the notion of improved survival as a consequence of ICT in patients suffering from transfusional iron overload. We have observed improvement in haematopoietic parameters in a proportion of patients with low-to-intermediate risk MDS treated with the oral iron chelator deferasirox (DFX). Our experimental results suggest that the haematopoietic response following treatment is likely to be a consequence of two distinct functions of DFX. Firstly, DFX inhibits NF-kappaB activity resulting in dampened inflammation in the bone marrow milieu. Secondly, iron chelation leads to mitochondrial dysfunction resulting in apoptosis of malignant clones whilst sparing normal haematopoietic stem cells. Our study provides for the first time a mechanistic basis for improved haematopoiesis in MDS patients treated with ICT.

Macrophage activation syndrome is excessive proliferation of macrophages associated with hemophagocytosis in bone marrow. It is characterized by fever >38.5oC for ≥7 days, splenomegaly, cytopenias (≥2 lineages), hypertriglyceridemia/ hypofibrinogenemia & hemophagocytosis. MAS occurying in neonatal period is very rare & only 2 sporadic case reports are available.We report a case of a neonate with MAS who presented with unremitting fever, hepatosplenomegaly, cytopenia, hyperferritinemia, with bone marrow suggestive of Hemophagocytosis.

BackgroundThe combination of fludarabine, cyclophosphamide, and rituximab (FCR) has produced improved response rates and a prolonged survival in patients with chronic lymphocytic leukemia (CLL). However, its therapeutic power is counterbalanced by significant hematologic toxicity. Persistent and new-onset cytopenia after the completion of FCR raise concern about disease recurrence, the development of therapy-related myeloid malignancies (TRMM), and infections.MethodsA total of 207 patients with CLL who achieved complete response, complete response with incomplete bone marrow recovery, or nodular partial remission were analyzed after frontline FCR therapy.ResultsThree months after the completion of therapy, 35% of patients had developed grade 2 to 4 cytopenia (according to Common Terminology Criteria for Adverse Events [version 4.0]). Factors found to be associated with cytopenia at 3 months after therapy were older age, advanced Rai stage disease, and lower baseline blood counts. Moreover, patients with cytopenia were less likely to have completed 6 courses of therapy with FCR. At 6 months and 9 months after therapy, the prevalence of grade 2 to 4 cytopenia was 24% and 12%, respectively. No differences in progression-free survival and overall survival were noted between cytopenic and noncytopenic patients or between patients with persistent and new-onset cytopenia. The prevalence of TRMM was 2.3% and did not differ significantly between cytopenic and noncytopenic patients or between those with persistent and new-onset disease. Late infections were more common in patients who were cytopenic at 9 months (38%) and were mostly bacterial (67%).ConclusionsCytopenia after the completion of therapy is a common complication of frontline FCR that improves over time, particularly for new-onset cases. The presence of persistent cytopenia (lasting up to 9 months after the completion of therapy) should not raise concern about CLL recurrence of the development of TRMM, but should

Background. Interleukin 18 (IL-18) is primarily a macrophage-derived, pro-inflammatory cytokine. As macrophages can act as effector cells in acute rejection, we examined the role of IL-18 in a rat model of acute renal allograft rejection. Methods. Life-sustaining orthotopic DA to Lewis allograft and Lewis-Lewis isograft kidney transplants were performed. In the same model, macrophage-depleted animals, achieved with liposomal-clodronate therapy, were also studied. Macrophage (ED1+) accumulation and IL-18 expression was assessed by immunohistochemistry. CD11b+ cells (macrophages) were isolated from kidney and spleen by micro beads. Real-time PCR was used to assess IL-18 and INF-gamma mRNA expression in tissue and cell isolates. Results. Allografts, but not isografts, developed severe tubulo-interstitial damage and increased serum creatinine by day 5 (P<0.001). Immunohistochemistry revealed a greater ED1+ cell accumulation in day 5 allografts compared with isografts (P<0.001). IL-18 mRNA expression was increased 3-fold in allografts compared to isografts (P<0.001). Accordingly, IL-18 protein was increased in allografts (P<0.001), and was predominantly expressed by ED1+ macrophages. CD11b+ macrophages isolated from allografts had a 6-fold upregulation of IL-18 mRNA expression compared to isograft macrophages (P<0.001). Macrophage depletion resulted in a marked attenuation of allograft rejection, ED1+ and IL-18+ cells were significantly reduced (P<0.05) as was IL-18 mRNA expression (29.28 +/- 2.85 vs 62.48 +/- 3.05, P < 0.001). INF-gamma mRNA expression (P < 0.01) and iNOS (P < 0.001) production were also significantly reduced in the macrophage-depleted animals. Conclusion. This study demonstrates that IL-18 is significantly increased during acute rejection and is principally produced by intra-graft macrophages. We hypothesize that IL-18 upregulation may be an important macrophage effector mechanism during the acute rejection process. © The Author [2005]. Published by Ox

Background. Interleukin 18 (IL-18) is primarily a macrophage-derived, pro-inflammatory cytokine. As macrophages can act as effector cells in acute rejection, we examined the role of IL-18 in a rat model of acute renal allograft rejection. Methods. Life-sustaining orthotopic DA to Lewis allograft and Lewis-Lewis isograft kidney transplants were performed. In the same model, macrophage-depleted animals, achieved with liposomal-clodronate therapy, were also studied. Macrophage (ED1+) accumulation and IL-18 expression was assessed by immunohistochemistry. CD11b+ cells (macrophages) were isolated from kidney and spleen by micro beads. Real-time PCR was used to assess IL-18 and INF-gamma mRNA expression in tissue and cell isolates. Results. Allografts, but not isografts, developed severe tubulo-interstitial damage and increased serum creatinine by day 5 (P<0.001). Immunohistochemistry revealed a greater ED1+ cell accumulation in day 5 allografts compared with isografts (P<0.001). IL-18 mRNA expression was increased 3-fold in allografts compared to isografts (P<0.001). Accordingly, IL-18 protein was increased in allografts (P<0.001), and was predominantly expressed by ED1+ macrophages. CD11b+ macrophages isolated from allografts had a 6-fold upregulation of IL-18 mRNA expression compared to isograft macrophages (P<0.001). Macrophage depletion resulted in a marked attenuation of allograft rejection, ED1+ and IL-18+ cells were significantly reduced (P<0.05) as was IL-18 mRNA expression (29.28 +/- 2.85 vs 62.48 +/- 3.05, P < 0.001). INF-gamma mRNA expression (P < 0.01) and iNOS (P < 0.001) production were also significantly reduced in the macrophage-depleted animals. Conclusion. This study demonstrates that IL-18 is significantly increased during acute rejection and is principally produced by intra-graft macrophages. We hypothesize that IL-18 upregulation may be an important macrophage effector mechanism during the acute rejection process. © The Author [2005]. Published by Ox

Only a few studies have addressed the cost-effectiveness of pharmacogenetics interventions in healthcare. Lack of health economics data on aspects of pharmacogenetics is perceived as one of the barriers hindering its implementation for improving drug safety. Thus, a recent Institute for Prospective Technological Studies (IPTS) study, entitled 'Pharmacogenetics and pharmacogenomics: state-of-the-art and potential socio-economic impact in the EU' included an explorative cost-effectiveness review for a pharmacogenetic treatment strategy compared with traditional medical practice. The selected case study examined the cost-effectiveness of thiopurine methyltransferase (TMPT) genotyping prior to thiopurine treatment in children with acute lymphoblastic leukemia (ALL). Information for the cost-effectiveness model parameters was collected from literature surveys and interviews with experts from four European countries (Germany, Ireland, the Netherlands and the UK). The model has established that TPMT testing in ALL patients has a favorable cost-effectiveness ratio. This conclusion was based on parameters collected for TPMT genotyping costs, estimates for frequency of TMPT deficiency, rates of thiopurine-mediated myelosuppression in TPMT-deficient individuals, and myelosuppression-related hospitalization costs in each of the four countries studied. The mean calculated cost per life-year gained by TPMT genotyping in ALL patients in the four study countries was €2100 (or €4800 after 3% discount) based on genotyping costs of €150 per patient. Cost per life-year gained is expected to further improve following the introduction of the wider use of TMPT genotyping and the availability of lower cost genotyping methods. Our analysis indicates that TPMT genotyping should be seriously considered as an integral part of healthcare prior to the initiation of therapy with thiopurine drugs. © 2006 Future Medicine Ltd. Chemicals / CAS: azathioprine, 446-86-6; mercaptopurine, 31441-78-8, 50-4

SCOPUS: ar.j, info:eu-repo/semantics/published

SCOPUS: ar.j, info:eu-repo/semantics/published