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The WHO classification provides the best diagnostic approach to myelodysplastic syndromes (MDS). However, biologic and analytic limitations have emerged in the criteria currently adopted to establish the diagnosis and to classify MDS. The provisional category of idiopathic cytopenia of undetermined significance (ICUS) has been proposed to describe patients in whom MDS is possible but not proven. To formulate a diagnosis of ICUS, a thorough diagnostic work-up is required and repeated tests should be performed to reach a conclusive diagnosis. Recent studies provided consistent evidence of age-related hematopoietic clones (clonal hematopoiesis of indeterminate potential; CHIP), driven by mutations of genes that are recurrently mutated in myeloid neoplasms and associated with increase in the risk of hematologic cancer. A subset of mutated genes, mainly involved in epigenetic regulation, are likely initiating lesions driving the expansion of a premalignant clone. However, in a fraction of subjects the detected clone may be a small malignant clone expanding under the drive of the detected and additional undetected mutations. In addition, several experimental evidences suggest the potential relevance of an abnormal bone marrow environment in the selection and evolution of hematopoietic clones in MDS. The spreading of massively parallel sequencing techniques is offering translational opportunities in the clinical approach to myeloid neoplasms. Although several issues remain to be clarified, targeted gene sequencing may be of potential value in the dissection between clonal myelodysplasia, nonclonal cytopenia, and clonal hematopoiesis arising upon aging or in the context of acquired marrow failure., (© 2015 by The American Society of Hematology. All rights reserved.)

Distinguishing hypoplastic myelodysplastic syndrome from aplastic anemia (AA) is challenging. In the present study, Japanese and Chinese pediatric hematologists and pathologists conducted a joint review of bone marrow (BM) smears and trephine biopsies in 100 children with acquired BM failure syndrome, using the criteria proposed in the 2008 edition of the World Health Organization classification of hematopoietic and lymphoid tissues. The final consensus for the diagnoses of 100 children was AA in 29 patients, refractory cytopenia of childhood (RCC) in 58 patients, and refractory cytopenia with multilineage dysplasia (RCMD) in 13 patients. No significant differences between Japanese and Chinese children were found with regards to clinical and laboratory findings, or the distribution of diagnoses. Patients with RCC/RCMD showed milder disease severity and BM hypocellularity than those with AA. To establish the provisional entities for RCC, it is essential to prospectively compare the clinical outcomes between AA and RCC groups in a large number of patients.

Hypoplastic BM disorders in children and adolescents comprise a broad spectrum of disorders. Acquired severe aplastic anemia (SAA), refractory cytopenia of childhood (RCC), a subtype of myelodysplastic syndrome (MDS), and inherited BM failure (IBMF) disorders are the main and most difficult hematological differential diagnoses. Whereas IBMF disorders can often be diagnosed by their clinical features and/or underlying genetic aberrations, the morphological distinction between SAA and hypocellular RCC has been controversial. The histopathological pattern of RCC consists of islands of immature erythroid precursors accompanied by sparsely distributed granulocytic cells. Megakaryocytes are significantly decreased or absent and, rarely, micromegakaryocytes are detected on immunohistochemistry. Because fatty tissue between areas of hematopoiesis can mimic SAA, 2 biopsies are recommended to facilitate the detection of representative BM spaces. Recent data indicate that the response to immunosuppressive therapy is inferior in RCC compared with SAA. Furthermore, approaches to allogeneic hematopoietic transplantation differ. Controlled prospective clinical studies in patients with hypoplastic BM failure disorders will require comprehensive guidelines for diagnosing SAA, RCC, and the different IBMF disorders.

Background: Intracerebral hemorrhage (ICH) is an unusual but serious complication of bleeding disorders. ICH is believed to follow thrombocytopenia, alterations in coagulation, and vascular fragility. Information regarding its distribution is nonconclusive, and the mechanism of bleeding is not fully understood. The aim of this study was to examine the clinical and neuroimaging features of ICH in patients with bleeding disorders to predict risk factors for this condition., Methods: All cases of ICH diagnosed from 1987 to 2004 were retrospectively identified using the centralized database of our institution. Cases were included whenever ICH was caused by a primary hematologic disorder. The clinical characteristics, neuroimages, and outcome were analyzed., Results: A total of 31 patients were identified. ICH was the initial presentation of the bleeding disorder in 9 patients. Overall, 71% had systemic bleeding concurrent to the ICH. All patients had altered mental status. In 45.2% of the patients simultaneous intracranial hemorrhages were found. Eight patients had recurrent ICH. Severe thrombocytopenia (platelet count < 10,000/mm(3)) was present in 41% and very low platelets (

Aplastic anemia (AA) is a disorder characterized by the presence of pancytopenia and a hypocellular bone marrow. Acquired pure red cell aplasia (PRCA), a part of a unique form of AA, is a rare condition of profound anemia characterized by the absence of reticulocytes and the virtual absence of erythroid precursors in the bone marrow. AA can be effectively treated by either stem cell transplantation or immunosuppressive therapy. However, PRCA has so far been treated by several different regimens which are largely empirically selected since so little control data are available. This issue focuses on the current progress in the treatment of acquired AA and PRCA.

Objective: To explore the relationship between CD8+ T-cell CD28 molecular expression in peripheral blood and TCM type in patients with chronic aplastic anemia (CAA)., Methods: Using flow cytometry to detect the CD28 expression in 45 in-patients or out-patients and 24 healthy subjects for control. And the relation with TCM type was analyzed from the immunological aspect., Results: (1) The levels of CD8, CD28, CD8+ CD28+ expression and CD8+ CD28+/CD8+ CD28- were all higher in the CAA patients than those in the healthy subjects (P < 0.05 or P < 0.01). (2) The levels of CD28, CD8+ CD28+ expression and CD8+ CD28+/CD8+ CD28- were all higher in the CAA patients of Shen-Yin deficiency type than those in the CAA patients of Shen-Yang deficiency type (P < 0.05 or P < 0.01)., Conclusion: (1) The abnormal high expression of peripheral blood co-stimulatory molecules CD28 suggested CD28 disorder may play an important role in immuno-pathogenesis of CAA. (2) The levels of peripheral CD28, CD8+ CD28+ expression and CD8+ CD28+/CD8+ CD28- can be taken as an objective indexes for TCM typing of CAA, which was disordered more severe in patients of Shen-Yin deficiency type than in those of Shen-Yang deficiency type.

The main cause of aplastic anaemia remains elusive. Germline mutations in the gene encoding the RNA component of telomerase (hTR) have been seen in the autosomal dominant form of dyskeratosis congenita--an inherited syndrome characterised by aplastic anaemia. By screening the hTR gene, we identified mutations in two of 17 patients with idiopathic aplastic anaemia, three of 27 patients with constitutional aplastic anaemia, but in none of 214 normal controls (p<0.0001). Furthermore, patients with hTR mutations had significantly shorter telomeres than age-matched controls (p=0.027). These data indicate that, in a subset of patients with aplastic anaemia, the disorder might be associated with a genetic lesion in the telomere maintenance pathway.

In most human cells, the average length of telomere repeats at the ends of chromosomes provides indirect information about their mitotic history. To study the turnover of stem cells in patients with bone marrow failure syndromes, the telomere length in peripheral blood granulocytes and lymphocytes from patients with aplastic anemia (AA, n = 56) and hemolytic paroxysmal nocturnal hemoglobinuria (n = 6) was analyzed relative to age-matched controls by means of fluorescence in situ hybridization and flow cytometry. The telomere lengths in granulocytes from patients with AA were found to be significantly shorter than those in age-adjusted controls (P =.001). However, surprisingly, telomere length in granulocytes from AA patients who had recovered after immunosuppressive therapy did not differ significantly from controls, whereas untreated patients and nonresponders with persistent severe pancytopenia showed marked and significant telomere shortening. These results support extensive proliferation of hematopoietic stem cells in subgroups of AA patients. Because normal individuals show significant variation in telomere length, individual measurements in blood cells from AA patients may be of limited value. Whether sequential telomere length measurements can be used as a prognostic tool in this group of disorders remains to be clarified. (Blood. 2001;97:895-900)

The authors evaluated results of treatment of 106 children with acquired aplastic anemia. The patients were divided into 3 groups depending on the severity of their disease. Thirty-nine patients were classified as very severe, 30 as severe and 37 as non-severe according to the modified Camitta criteria. Among them, 47 children were treated with oxymetholone and prednisolone. In this group 32 died. Antilymphocyte globulin (ALG) was given to 48 patients and 20 received cyclosporin A (CsA). The results obtained by these two methods are nearly the same and 5 year survival was 61% and 59% respectively. Bone marrow was transplanted in only one child, who is still in complete remission. Statistical analysis showed a steady increase in incidence of aplastic anemia in the years 1987-1989, which might coincide with the Czarnobyl explosion. However, further research is required to prove this point.

Hematopoietic function of some aplastic anemia (AA) patients is dependent on the administration of cyclosporine (CyA). To investigate whether certain HLA class II genes are associated with susceptibility to such CyA-dependent AA, we determined the HLA class II alleles of 59 AA patients treated with CyA. Among 26 patients successfully treated with CyA, 13 required a small dose of CyA to maintain stable hematopoiesis. Of these 13 AA patients, 10 shared an HLA class II haplotype of DRB1*1501-DQA1*0102-DQB1*0602. None of the 13 responders who obtained a sustained remission off CyA therapy possessed this haplotype. In the 10 patients who shared the HLA class II haplotype, single-strand conformation polymorphism analysis of each gene fragment of this haplotype failed to detect a polymorphism in the nucleotide sequence. When the AA patients were assessed for their likelihood to respond to CyA therapy, the response rate in patients with this haplotype (71%) was significantly higher than that of patients with another haplotype associated with HLA-DR2, DRB1*1502-DQA1*0103-DQB1*0601 (36%) and that of patients without HLA-DR2 (35%). These findings indicate that the CyA-dependent response of AA is closely related to an HLA class II haplotype of DRB1*1501-DQA1*0102-DQB1*0602 and suggest that, in AA patients with this haplotype, immune mechanisms play an important role in the pathogenesis of bone marrow failure.

We reviewed the clinical courses of 38 children with acquired aplastic anemia (AA). The patients were classified according to the severity criteria by the Japanese Ministry of Health and Welfare (JMHW) Study Group (22 severe, 15 moderate, 1 mild). Early death was observed only in severe cases. Eight of the non-severe cases progressed to severe in 0.5-125 months, and the long-term survival rate of non-severe AA did not differ from that of severe AA. The frequency of lymphocytes in the bone marrow was significantly higher, and the peripheral blood neutrophil count was lower in patients who died within a year, and these patients should be treated as very severe. These findings suggest that the JMHW Study Group criteria are useful for identifying AA patients with a poor prognosis, but even non-severe cases should be repeatedly evaluated. Sixteen of the 33 patients treated with corticosteroids and/or anabolic steroids (AS) showed hematological recovery. Bolus methylprednisolone (mPSL) therapy was effective in one of the 8 patients. Allogenic marrow transplant (BMT) was performed on 3 patients. One died from sepsis and engraftment was not achieved in the other two. Trilineage recovery was obtained in 3 of 6 patients treated with rhG-CSF and rhEPO with or without AS, and hemopoiesis has been maintained 6-12 months after discontinuation in 2 cases. In the other 3 patients, the neutrophil count showed transient increase. Therefore, the treatment for severe AA patients, who have no sibling donor for BMT, should be started with the combination therapy including these cytokines.

Growth and differentiation of hematopoietic progenitor cells is regulated by a complex network of stimulatory and inhibitory cytokines. Bone marrow failures can be due to a decrease of stimulators or an increase of inhibitors. T cells produce both, hematopoiesis stimulating and inhibiting cytokines. Therefore, a role of T cells in regulating hematopoiesis can only be assumed if the gene expression of these antagonistic acting cytokines can be differentially induced in T cells. To establish a model of selective cytokine induction, we investigated the induction of IFN gamma as inhibitor and GM-CSF as stimulator of hematopoiesis in T cells. Our results showed that IFN gamma mRNA accumulates in T cells which have been pre-activated via the signal transduction unit CD3, but not in unstimulated T cells. This accumulation depends on the expression of the high affinity IL2 receptor which is including the IL2 receptor alpha-chain (IL2R alpha, CD25). In a study on children with constitutional (CAA) versus acquired aplastic (EAA) anemia, we investigated the relevance of this model for the pathogenesis of aplastic anemia in childhood. We compared the following parameters: 1. Incidence of hematopoietic progenitor cells and cloning efficiency, 2. activation status and IL2R alpha expression of bone marrow T cells, 3. T cell cytokine expression profile. Our results show: 1. The relative incidence of bone marrow progenitor cells is decreased in children with CAA and normal in children with EAA. 2. Clonogenic growth of hematopoietic progenitor cells is suppressed in children with EAA.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemopoietic progenitor cells (BFU-E, CFU-E and CFU-GM) of 69 cases of aplastic anemia were cultured in vitro while the sensitivity of CFU-E and BFU-E to androgen was assayed. The suppressive effect of peripheral blood mononuclear cell (PBMNC) from patients on normal CFU-GM growth was also studied. Hence 69 cases of aplastic anemia were divided into three types: 10 cases of stem cell deficiency type, 30 cases of immuno-mediated type and 29 cases of androgen response type. According to above classification, different treatment programs were practiced using both TCM and western medicine. In the androgen response type, androgen and TCM were used and the effective rate reached 92.3%. In the immuno-mediated type, in addition to TCM. Immunosuppressive agents were cautiously used and the effective rate was 70.6%. As for the stem cell deficiency type, 10 patients' conditions were usually very severe so comprehensive therapeutical means were adopted and 3 cases were improved. The overall response rate of these three was 73.2%. These results showed that the treatment program under the direction of classification have greatly improved the curative effect.

The treatment of 77 children suffering from acquired aplastic anemia (AAA) in the Petersburg Pediatric Hematological Center allowed the authors to distinguish three groups of patients according to the disease severity: severe, moderate and mild. The groups differed by clinicohematological parameters and treatment results. With reference to the above classification conventional combined treatment with hormones and splenectomy is uneffective in groups 1 and 2, but is able to induce remission in half the patients with mild disease. Immunosuppression with antilymphocytic globulin and large-dose methylprednisolone markedly contributed to survival prolongation in severe and moderate AAA (69 and 90% of cases with long-term remissions, respectively), being a failure in group 1 patients who are primarily scheduled for bone marrow transplantation.

The T-lymphocyte subsets of 38 patients with chronic aplastic anemia (CAA) were measured by monoclonal antibody (McAb) and ABC method and the relationship of T-lymphocyte subsets and symptom complex groups by traditional Chinese medicine theory were also analysed. It was shown that the T subsets of patients with CAA have remarkable changes: Ts (41.3 +/- 11.2%) increased more than the control (22.9 +/- 4.5%), Th/Ts decreased significantly more than the normal control (0.98 +/- 0.38 to 1.59 +/- 0.38). From the group of deficiency of both vital energy and blood to the group of deficiency of Kidney-yang to the group of deficiency of Kidney-Yin to the group of deficiency of both Kidney-Yang and Kidney-Yin, the Th lymphocyte gradually decreased, Ts lymphocyte successfully increased (from 33.8 +/- 7.9% to 57.7 +/- 7.5%), Th/Ts ratio declined (from 1.29 +/- 0.36 to 0.57 +/- 0.19). The Th/Ts ratio of the latter two groups decreased more than the former two groups (P less than 0.01). These results indicated that the T lymphocyte subsets and symptom complex group of patients with CAA were closely related and when deficient Yang affects Yin the immunologic function of body has a more obvious change. This revealed the connotation of Kidney-Yin and Kidney-Yang on the immuno-regulating cells (T lymphocyte subsets) level.

Aplastic anemia can be classified distinctively three types as progenitor depletive; immunosuppressive and androgenic sensitive. Using bone marrow culture in vitro which had been accomplished in our laboratory, 53 patients with aplastic anemia were also classified according to TCM term in three groups as Yin deficiency, Yang deficiency and both Yin and Yang deficiency, and the correlation was observed between TCM classification and lab character of these patients. The results showed that the number of CFU-GM, CFU-E and BFU-E in Yang deficiency group was significantly higher than that in the other two groups (P less than 0.01 and P less than 0.05). It also showed that the sensitivity of progenitor cells to androgenic hormones of Yang deficiency group was preferential to all (P less than 0.005 and P less than 0.05). The percentage of immunosuppressive type of aplastic anemia in Yin deficiency group was much higher than those in the other two groups (P less than 0.005). These observations suggested that TCM classification for aplastic anemia in this paper has objective material foundation.

According to the cellularity in the first bone marrow aspirate, 541 cases of aplastic anemia (AA) diagnosed in the Peking Union Medical College Hospital were divided into two groups--hypoplastic and hyperplastic. Comparison of the transformation, remission and long-term survival rates in the two groups showed the following results. (1) Transformation: In the hypoplastic group, 60% of the cases maintained the original degree of proliferation, 34% was transformed to hyperplastic, 3% had repeated transformation and 3% became leukemic. In the hyperplastic group, 44% maintained the original degree of proliferation, 44% was transformed to hypoplastic, 9.3% had repeated transformation and 2.7% became leukemic. (2) Remission rate: The total remission rate was 15.9% in the hypoplastic and 14.6% in the hyperplastic group. (3) Long-term survival rate: The 1-, 5- and 10-year survival rates were 70.43%, 57.66% and 51.51% in the hypoplastic group, while they were 86.7%, 71.24% and 63.34% respectively in the hyperplastic with statistical significance (P less than 0.01). It is emphasized that AA can not be ruled out if there is hyperplasia in the bone marrow smear taken for the first time or in several smears taken from the same site. Smears taken periodically from different sites are essential for correct diagnosis.

The biphasic shape of the survival curve of 99 patients with aplastic anemia suggested that there may be at least two subgroups of patients with this disease, one with a very short survival and another with a longer survival. Patients who survived for 4 mo or less after the first clinic visit (group A) were different from the patients who survived longer (group B) with respect to their modes of onset, sex, intervals from the onset of symptoms to first clinic visit, and initial hematologic values. These differences suggested that short survival could be predicted from data available at the first contact with the physician. From these measurements, a prognostic index could be calculated which was useful in identifying the patients in group A. Although this method of prognostication needs further testing, if validated, it may prove useful in selecting patients for therapeutic trials and could explain the divergent results in previous studies of androgen treatment of aplastic anemia. When our androgen-treated subjects were compared with subjects with a similar prognostic index who had not received androgens, a beneficial effect of androgen therapy on survival could not be demonstrated.

New automated blood cell analyzers provide an index of red cell volume distribution width (RDW) or heterogeneity and a histogram display of red cell volume distribution. We have developed a classification of red cell disorders, based on mean corpuscular volume (MCV) or red cell size, heterogeneity, and histograms, to guide diagnosis from the peripheral blood analysis. The distinction of iron deficiency anemia from heterozygous thalassemia or the anemia of chronic disease and the detection of early iron and folate deficiency is improved. Red cell volume distribution histograms identify red cell fragmentation or agglutination, dimorphic populations, and artifactual counting of lymphocytes as red cells. We recommend the use of these new variables in the initial classification of anemia by the practicing physician.

New diagnostic criteria for the diagnosis of the various myelodysplastic syndromes (MDS) are proposed, and a detailed description is given of the features that may help define MDS. Five MDS are described: (1) refractory anaemia (RA), (2) RA with ring sideroblasts, (3) RA with excess of blasts (RAEB), (4) chronic myelomonocytic leukaemia (CMML), and (5) RAEB 'in transformation'. One of the main distinguishing features of these conditions is the proportion of blast cells in the peripheral blood (PB) and/or bone marrow (BM). The morphological features of the blast cells that are of diagnostic importance have been redefined. In RA, with or without ringed sideroblasts, there are fewer than 1% of blasts in the PB and fewer than 5% in the BM; RAEB is defined as having between 5% and 20% of blasts in the BM and fewer than 5% in the PB; RAEB in transformation (a newly defined category) will be considered when any of the following features is present: (i) more than 5% of blasts in the PB, (ii) 20-30% in the BM, and (iii) the presence of Auer rods in granulocyte precursors in BM or PB. In accordance with these newly defined criteria, it is now proposed that over 30% of bone marrow blasts will suffice for the diagnosis of acute myeloid leukaemia (AML) in any of its forms (M1-M6). The proposed descriptions of the MDS should facilitate the interpretation of data emerging from cytogenetic and bone marrow culture studies and the search for features of possible prognostic significance. Recognition of the new category, RAEB in transformation, may throw light on the pathogenesis of AML.

Thirty-four children with aplastic anaemia who presented between 1964 and 1984 are reviewed. Their ages ranged from one to 13 years (median, seven years). Twelve children had constitutional aplasia; nine of 11 children had responded to androgen and corticosteroid therapy. However, by actuarial analysis, only 48% would survive at five years and only 16% after 10 years. Twenty-two children had acquired aplasia; in 16 children this had no obvious cause. By means of the criteria of the International Aplastic Anemia Study Group, patients were categorized into severe and non-severe groups at diagnosis. Severe disease was present at diagnosis in nine of 22 children with acquired aplasia but in no child with constitutional disease. Two patients with severe acquired aplasia showed a transient response to androgen or corticosteroid therapy, whereas five of nine children with acquired aplasia which was not severe showed a sustained response to such therapy. A significant difference in survival times was seen between severe and non-severe groups at five years; two (17%) of nine children with severe aplasia survived, compared with eight (67%) of 12 children with non-severe aplasia. Three children with severe aplasia who were treated with antilymphocyte globulin showed no improvement. Of five children who underwent bone-marrow transplantation for severe or progressive disease, four survived. It is concluded that bone-marrow transplantation, as a matter of urgency, is the treatment of choice for severe acquired aplastic anaemia; it is also recommended for mild acquired or constitutional aplasia when progressive disease is present or where transfusion therapy will be required. Antilymphocyte globulin is an alternative form of treatment for acquired disease. Androgen therapy is effective in the treatment of non-severe acquired and constitutional aplastic anaemia.

The myelodysplastic syndromes (MDS) are a group of closely related disorders characterized by chronic cytopenias with cellular marrow, poor prognosis and refractoriness to treatment. We studied 101 consecutive cases of MDS diagnosed over a 7-year period. Peripheral blood (PB) and bone marrow (BM) samples were reviewed and classified according to the proposals of the French-American-British (FAB) cooperative group for MDS. The combined analysis of the initial laboratory features and qualitative haematological abnormalities readily allowed the distinction between the different subgroups. Thirty-two of 79 cases (40.5%) evolved towards other diseases, frequently acute leukaemia (24/79, 30%), or transformed into other MDS (7/79, 9%). In five cases, initially classified as refractory anaemia (RA) or refractory anaemia with ring sideroblasts (RAS), a transitory change to another type of MDS--two chronic myelomonocytic leukaemias (CMML), two refractory anaemias with excess of blasts (RAEB) and one refractory anaemia with excess of blasts 'in transformation' (RAEB-t)--was observed before the evolution towards acute leukaemia. This provides a new link between all these syndromes and increases the number of transitions to other MDS. Overall prognosis was very poor, with differences between subgroups. RA had the best prognosis whereas RAEB-t had the worst one. This study shows that the FAB classification is readily usable and defines well-characterized subgroups of MDS, although there are frequent transitional forms, and as the natural history of the MDS unfolds they may convert into another. The actual poor prognosis and the frequent evolution towards acute leukaemia makes necessary to investigate new methods of treatment for these disorders.