Performance evaluation of a novel artificial intelligence (AI)-assisted digital microscopy system for the routine analysis of bone marrow aspirates.

Bone marrow aspiration (BMA) smear analysis is essential for diagnosis, treatment and monitoring of a variety of benign and neoplastic hematological conditions. Currently this analysis is performed by manual microscopy. We conducted a multi-center study to validate a computational microscopy approach with an artificial intelligence (AI)-driven decision support system. A total of 795 BMA specimens (615 Romanowsky-stained and 180 Prussian blue-stained) from patients with neoplastic and other clinical conditions were analyzed, comparing the performance of the Scopio Labs X100 Full Field BMA system (test method) with manual microscopy (reference method). The system provided an average of 1385±536 (range 0-3131) cells per specimen for analysis. An average of 39.98±19.64 fields of view (range 0-140) per specimen were selected by the system for analysis, of them 87±21% (range 0-100%) were accepted by the qualified operators. These regions were included in an average of 17.62±7.24 regions of interest (range 1-50) per specimen. The efficiency, sensitivity, and specificity for primary and secondary marrow aspirate characteristics (maturation, morphology, and count assessment), as well as overall inter-user agreement, were evaluated. The test method showed high correlation with the reference method for comprehensive BMA evaluation, both on Romanowsky (90.85% efficiency, 81.61% sensitivity; specificity 92.88%) and Prussian blue (90.0% efficiency, 81.94% sensitivity; 93.38% specificity) stained samples. The overall agreement between the test and reference method for BMA assessment was 91.1%. For repeatability and reproducibility, all standard deviations and coefficients of variation values were below the pre-defined acceptance criteria both for discrete measurements (CV below 20%) and for differential measurements (SD below 5%). The high degree of correlation between the digital decision support system and manual microscopy demonstrates the potential of this system to provide a high-quality, accurate digital BMA analysis, -expediting expert review and diagnosis of BMA specimens, with practical applications including remote BMA evaluation, and possibly new opportunities for the research of normal and neoplastic hematopoiesis.

Successful treatment with plasma exchange in life-threatening hyperhemolytic syndrome unrelated to sickle cell disease.

INTRODUCTION: Hyperhemolytic syndrome (HHS) is a severe form of delayed transfusion reaction primarily described in sickle cell anemia patients which is characterized by a hemoglobin decrease to pre-transfusion levels or lower, often with reticulocytopenia and no evidence of auto- or allo-antibodies. CASE PRESENTATION: We present two cases of severe HHS in patients without sickle cell anemia refractory to treatment with steroids, immunoglobulins, and rituximab. In one case, temporary relief was achieved with eculizumab. In both cases, plasma exchange resulted in a profound and immediate response allowing for splenectomy and resolution of hemolysis. DISCUSSION/CONCLUSION: We discuss the pathophysiology of HHS, its presentation and treatment and expand on the possible role of plasma exchange in this setting.

Thalassaemia-A global view.

The thalassaemias are a group of genetic disorders of haemoglobin which are endemic in the tropics but are now found worldwide due to migration. Basic standard of care therapy includes regular transfusions to maintain a haemoglobin level of around 10 g/dL, together with iron chelation therapy to prevent iron overload. Novel therapies, bone marrow transplantation, and gene therapy are treatment options that are unavailable in many countries with stressed economies. This Wider Perspectives article presents the strategies for management of an adolescent refugee patient with beta thalassaemia, as it would be performed by expert haematologists in six countries: Italy, Lebanon, Oman, the Sudan, Thailand and the United States. The experienced clinicians in each country have adapted their practice according to the resources available, which vary greatly. Even in the current modern era, providing adequate transfusions and chelation is problematic in many countries. On the other hand, ensuring adherence to therapy, particularly during adolescence, is a similar challenge seen in all countries. The concluding section highlights the disparities in available therapies and puts the role of novel therapies into a societal context.

Intravenous iron: do we adequately understand the short- and long-term risks in clinical practice?

Intravenous (IV) iron as a therapeutic agent is often administered but not always fully understood. The benefits of IV iron are well proven in many fields, particularly in nephrology. IV iron is beneficial not only for true iron deficiency but also for iron-restricted anaemia (functional iron deficiency). Yet, the literature on intravenous iron has many inconsistencies regarding its adverse effects. Over the last several years, newer forms of iron have been developed, leading to the more regular use of iron and in larger doses. This review will summarize some of the older and newer literature regarding the differences among iron products, including the mechanisms and frequency of their adverse events (AEs). The pathway and frequency of an underrecognized adverse event (hypophosphataemia) will be discussed. Recent insights on infection risk and iron handling by macrophages are examined. Potential but presently unproven risks of iron overload due to IV iron are discussed. The impact of these on the risk:benefit ratio and dosing of intravenous iron are considered in different clinical settings, including pregnancy and cancer. IV iron is an essential component of the therapy of anaemia and understanding these issues will enable more informed treatment decisions and knowledgeable use of these drugs.

Chronic Lymphocytic Leukemia and Myelofibrosis.

BACKGROUND: Chronic lymphocytic lymphoma (CLL) can be associated with several malignancies, but rarely with myelofibrosis. Only isolated case reports in the literature described the association between CLL and primary myelofibrosis (PMF) in the same patient. OBJECTIVES: We describe a case of CLL characterized by the development of PMF and a review of literature. METHODS: We describe an 86-year-old female diagnosed as having CLL and followed by the development of splenomegaly and progressively rising LDH levels 27 months later. A bone marrow biopsy was consistent with the diagnosis of PMF, with positive JAK-2 V617F mutation. We also review the clinical and molecular characteristics of patients with CLL and PMF. RESULTS: Patients with CLL and PMF are usually older. A lead diagnosis of CLL harbored by PMF is the most common clinical course, although concomitant diseases may occur in 31.7% of patients. JAK-2 V617F mutation can be found in 48.7% of patients. CONCLUSION: This case reported here constitutes an unusual situation of CLL characterized by the development of PMF. Etiologic and pathogenic associations-the role of t (1; 6) and JAK-2 V617F mutation-are discussed.

Haplotype analysis of α-thalassemia chromosomes reveals heterogeneity and multiple founders in Ashkenazi Jews.

α-Thalassemia (α-thal) is among the world's most common single gene disorders, generally attributed to a selective advantage of heterozygotes against malaria mortality. A high frequency of -α3.7 deletion heterozygosity has been previously reported in Ashkenazi Jews despite lack of obvious malarial selection pressure in this population. Using haplotype and -α3.7 subtype analysis we analyzed a subset of -α3.7 homozygotes from various Israeli ethnic groups. We found a high frequency of the common Ia haplotype in Yemenite Jews and Arabs (54% and 13% respectively). Ashkenazi Jews exhibited a high frequency of IIIb alleles (67%) previously reported only in Aboriginal Australians and not found in other Israeli ethnicities. Both Yemenites and Ashkenazim carried the rare IIh alleles (18% and 15% respectively). These results may suggest multiple founder effects in Ashkenazi Jews as well a common founder for both Yemenite and Ashkenazi Jews.

Atypical presentations of thrombotic thrombocytopenic purpura: a diagnostic role for ADAMTS13.

Thrombotic thrombocytopenic purpura (TTP) is an acute, life threatening disease. Only a minority of patients expresses the complete clinical presentation and unusual manifestations can occur. Demonstration of low activity levels of ADAMTS13 (<5 %) is highly specific for the diagnosis of TTP. This study reports a series of five cases of TTP presenting with a thrombotic event and no hematological findings. Detailed chart reviews on these patients were conducted. We identified two patients whose first attack of TTP presented as a thrombotic episode without microangiopathic hemolytic anemia and thrombocytopenia, only to be diagnosed as TTP days later, after the appearance of hematological signs. We also describe three cases of classical TTP relapsing atypically as cerebrovascular accidents without hematological signs. Low levels of ADAMTS13 activity were detected and facilitated the diagnosis. The neurological manifestations disappeared concurrent with normalization of ADAMTS13 activity level after plasma exchange. This study underscores the importance of having a high clinical suspicion of TTP in cases of thrombosis even without hematological abnormalities in patients with previous attacks of TTP. In this clinical scenario, measurement of ADAMTS13 activity is important for diagnosis and early administration of treatment.

The role of N-acetylcysteine in the treatment of thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is an acute, thrombotic microangiopathy with a high mortality rate if left untreated. Plasma exchange (PEX) is the current standard of care. However, a significant number of patients are refractory to this treatment. N-acetylcysteine (NAC) was recently suggested as a potential therapeutic adjunct for patients with TTP. This study reports a series of three patients with TTP successfully treated with NAC in addition to standard therapy. Detailed chart reviews on these patients were conducted. We discuss clinical features, laboratory findings and management of three patients who presented with microangiopathic hemolytic anemia and thrombocytopenia. Anti-ADAMTS13 antibodies and low levels of ADAMTS13 were detected and confirmed the diagnosis of acquired TTP. Based upon their severe presentation or lack of response to initial treatment with PEX, corticosteroids and other immunosuppressive agents, NAC was added. Under this combined treatment, all three patients hada significant clinical improvement of symptoms with concurrent normalization of platelet count and ADAMTS13 activity level. This report highlights the potential therapeutic utility of NAC in the treatment of TTP. Randomized controlled studies will be required to better characterize the risk-to-benefit ratio of NAC in the treatment of TTP.

Thalassemia 2016: Modern medicine battles an ancient disease.

Thalassemia was first clinically described nearly a century ago and treatment of this widespread genetic disease has greatly advanced during this period. DNA-based diagnosis elucidated the molecular basis of the disease and clarified the variable clinical picture. It also paved the way for modern methods of carrier identification and prevention via DNA-based prenatal diagnosis. Every aspect of supportive care, including safer blood supply, more regular transfusions, specific monitoring of iron overload, parenteral and oral chelation, and other therapies, has prolonged life and improved the quality of life of these patients. Significant advances have also been made in allogenic bone marrow transplantation, the only curative therapy. Recently, there has been a rejuvenated interest in studying thalassemia at the basic science level, leading to the discovery of previously unknown mechanisms leading to anemia and enabling the development of novel therapies. These will potentially improve the treatment of, and possibly cure the disease. Pathways involving activin receptors, heat shock proteins, JAK2 inhibitors and macrophage targeted therapy, among others, are being studied or are currently in clinical trials for treating thalassemia. Novel types of genetic therapies are in use or under investigation. In addition to the challenges of treating each individual patient, the longer survival of thalassemia patients has raised considerations regarding worldwide control of thalassemia, since prevention is not universally implemented. This review will trace a number of the original medical milestones of thalassemia diagnosis and treatment, as well as some of the most recent developments which may lead to innovative therapeutic modalities.