bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact Of Age On Toxicity Associated With Chemotherapy For Acute Lymphoblastic Leukaemia (ALL): Results From The UK Prospective Study UKALL2003
Authors: Hough Rachael E. , Rowntree Clare , Wade Rachel , Goulden Nicholas , Mitchell Chris , Vora Ajay J. 
Published: October 2019

Abstract
Despite the substantial improvements made in the outcomes of paediatric ALL, with ‘cure' rates now in excess of 90%, survival in teenage and young adult (TYA) patients has remained inferior. The reasons for this are likely multifactorial, including tumour biology, toxicity, compliance, access to clinical trials and protocol (adult or paediatric) used. We report the toxicity profiles observed in children, teenagers and young adults treated on the UK intensive, minimal residual disease (MRD) directed ALL protocol, UKALL2003.
Of a total of 3126 patients treated, 1520 patients were under 5 years old, 767 were aged 5-9 years, 610 aged 10-15 years and 229 aged 16-24 years, with a median overall follow-up of 4 year and 10 months. The risk of serious adverse events (SAEs) was higher in patients older than 10 years (56% in 10-15 year olds, 53% in 16-24 year olds) compared to those aged 9 or younger (30% in under 5 years and 31% in 5-9 years)(p<0.0001), with no difference in the those aged 16-24 compared to younger teenagers (p=0.5). The incidence (per number of patients in each group) and distribution of toxicities according to age group is summarised in the table.Table 1Age in years<55-910-1516-24AllTotal number of patients1520767610229 NB: 56 pts≥20 years3126Infection n (%)328 (21.6%)130 (17.0%)145 (23.8%)72 (31.4%)675 (21.6%)Asaparaginase n (%)57 (3.8%)57 (7.4%)64 (10.5%)31 (13.5%)209 (6.7%)Methotrexate n (%)100 (6.6%)74 (9.6%)123 (20.2%)33 (14.4%)330 (10.6%)Steroid n (%)54 (3.6%)37 (4.8%)141 (23.1%)52 (22.7%)284 (9.0%)Vincristine n (%)34 (2.2%)11 (1.4%)22 (3.6%)7 (3.0%)74 (2.4%)Other SAEs94 (6.2%)42 (5.5%)90 (14.8%)25 (10.9%)251 (8.0%)
The incidence of certain toxicities including viral infection (5.3%), asparaginase hypersensitivity (1.9%) and vincristine neurotoxicity (2.1%) appeared equivalent across all age groups. Avacular necrosis was seen predominantly in adolescents (83% of 147 events in 10-19 year olds) and was rare in those younger than 10 years (n=18) or older than 20 years (n=7). Asparaginase thrombotic events increased in frequency with increasing age (1.5% in under 5 years, 3.3% in 5-9 years, 4.4% in 10-15 years and 8.3% in 16-24 year olds)(p<0.0001). All other toxicities were more frequently observed in over 10 year olds compared to patients aged 9 or younger, with no difference between 16-24 year olds and 10-15 year olds.
The impact of age on SAEs associated with intensive ALL chemotherapy varies according to specific toxicities. In general, toxicity is higher in those over 10 years compared to younger patients, with no excess toxicity in those aged 16-24 compared to 10-15 years. However, specific toxicities may increase with increasing age (thrombosis), be restricted to adolescence (AVN) or be unrelated to age (vincristine neurotoxicity, asparaginase hypersensitivity).

Disclosures:
No relevant conflicts of interest to declare.
Unique and Potent Tumor Specific Antibodies in Graft Versus Leukemia Responses
Authors: Gillissen Marijn A. , Yasuda Etsuko , Levie Sophie , Bakker Arjen Q , Kedde Martijn , Claassen Yvonne B , Huisman Cynthia , Spits Hergen , Beaumont Tim , Hazenberg Mette D. 
Published: October 2019

Abstract
Introduction
Acute myeloid leukemia (AML) is a high-risk malignancy with a poor prognosis. Allogeneic hematopoietic stem cell transplantation (HSCT) can be curative if it induces a potent graft versus leukemia (GvL) response. GvL responses and graft versus host disease (GvHD) are typically considered T cell mediated, because T cell depletion from hematopoietic stem cell grafts reduces the risk of GvHD at the cost of leukemia relapse. In addition, depletion of B-lymphocytes with rituximab has led to amelioration of GvHD in a number of studies suggesting that B cells are also important in the pathophysiology of GvHD and, in analogy, in GvL responses. However, the characteristics of the antibodies produced by these leukemic specific B cells have not yet been studied.
Methods
We selected three patients with high-risk myelomonocytic leukemia who remained disease free years after allogeneic HSCT, from whom we established clonal human B cell lines, using a unique and innovative technology that was developed in our laboratory (Kwakkenbos ea, Nat Med 2010). These B cell lines, that concomitantly express immunoglobulin on their membranes and secrete antibodies, were used to select antibodies specific for cell surface antigens on AML cell lines with similar morphologic and immunophenotypic characteristics as the patients’ leukemic blasts, using a FACS based assay.
Results
From each patient, several AML specific B cell clones were retrieved. Their antibodies recognized surface antigens on primary AML blasts derived from multiple patients and on AML cell lines, but not on healthy bone marrow, peripheral blood mononuclear cells or tissues such as liver, skin and colon. The majority of the antibodies were of the IgG3 isotype. Approximately 40% of the AML-specific antibodies induced direct death of cultured AML cell lines and of primary AML blasts. The cell death pathway induced by these cytotoxic antibodies was oncotic rather than apoptotic.
Conclusion
Our data demonstrate that high-risk AML patients with a potent GvL response mount robust antibody responses against surface antigens that are specifically expressed on tumor cells and binding of these antibodies induces direct cell death. The targets recognized by the recovered antibodies are also expressed on leukemic blast from other patients suggesting evidence for a common immune mechanism responsible for AML clearance. Our findings suggest that antibody responses are important in GvL and open up new ventures for specific antibody treatment of AML patients.

Disclosures
No relevant conflicts of interest to declare.
A Prospective Randomized Comparison of Cyclophosphamide Versus Fludarabine in Addition of Antithymocyte Globuline for Allogeneic Hematopoietic Cell Transplantation in Patients with Adult Severe Aplastic Anemia; Interim Analysis
Authors: Kim Hawk , Lee Won-Sik , Kim Yeo-Kyeoung , Joo Young-Don , Park Jinny , Jung Chul Won , Jo Jae-Cheol , Lee Jung-Hee , Lee Je-Hwan , Kim Dae-Young , Lee Kyoo-Hyung 
Published: October 2019

Abstract

Our previous study showed that a less toxic regimen comprising reduced cyclophosphamide (Cy), fludarabine and anti-thymocyte globulin (ATG) (Cy-Flu-ATG), was less toxic for allogeneic hematopoietic cell transplantation (alloHCT) compared with standard Cy-ATG in patients with adult severe aplastic anemia (AA). We postulated that replacing Cy with Flu (Flu-ATG) would be more beneficial. Therefore we performed a randomized phase III study to compare the regimen-related toxicities (RRTs) of two different conditioning regimens: Cy-ATG vs. Flu-ATG. We present the interim alaysis. Patients in the Cy-ATG arm received Cy at 200 mg/kg. Those in the Flu-ATG arm received fludarabine (Flu) at 180 mg/m2. A total of 36 patients (21 in the Cy-ATG and 15 in the Flu-ATG) were enrolled. The basic patientsÕ characteristics were similar between both arms except for donor type and HLA-matching. There were more unrelated donor (38.1% vs. 73.3%; p=0.037) and HLA mis-matching (0% vs. 40%; p=0.001) in Flu-ATG arm. All predefined RRTs were similar between Cy-ATG and Flu-ATG (33.3% vs. 33.3%; p=1.000). There was no primary engraftment failure in both arms and only one patients in Cy-ATG died of treatment-related hepatic toxicity before engraftment. Also there were no differences between Cy-ATG and Flu-ATG arms in terms of secondary engraftment failure (20% vs. 20%; p=1.000), hepatic sinusoidal obstruction syndrome (0% vs. 0%; p=1.000), hemorrhagic cystitis (4.8% vs. 0%; p=1.000), pulmonary complications (12.5% vs. 16.7%; p=1.000). The incidence of acute graft-versus-host disease (GvHD) (14.3% vs. 20.0%; p=0.677) and chronic GvHD (11.8% vs. 7.7% ; p=1.000) were also similar. The 3-year survival rate did not differ (77.3% vs. 77.0%; p=0.995; Figure 1). Flu-ATG can be
Figure 1 promising in terms of RRT without increasing engraftment failure in Flu-ATG arm when considering more unrelated and HLA-mismaching patients were enrolled. We will continue this phase III trial. Figure 1. promising in terms of RRT without increasing engraftment failure in Flu-ATG arm when considering more unrelated and HLA-mismaching patients were enrolled. We will continue this phase III trial.

Disclosures
No relevant conflicts of interest to declare.
Interaction of Hemoglobin Lepore with Sickle Cell Trait and Microcythemia (Thalassemia) in a Southern Italian Family
Authors: SILVESTRONI EZIO , BIANCO IDA , BAGLIONI CORRADO 
Published: October 2019

Abstract
An abnormal hemoglobin has been observed in a southern Italian family together with sickle cell hemoglobin and thalassemia (microcythemia). The hematologic study has shown that all the carriers of the abnormal hemoglobin are microcythemic. The hemoglobins of these individuals have been studied by paper, starch gel, starch block and agar gel electrophoresis. The abnormal hemoglobin has been isolated and identified by fingerprinting as Hb LeporeBoston. The combination of Hb LeporeBoston with thalassemia and sickle cell trait has been observed in members of this family. The hematologic and biochemical implications of the Hb Lepore/thalassemia disease are discussed.
A Quantitative Immunogenetic Study of Gene Suppression Involving A1 and H Antigens of the Erythrocyte without Affecting Secreted Blood Group Substances. The ABH Phenotypes Ahm and Ohm
Authors: SOLOMON JOEL M. , WAGGONER ROBERT , LEYSHON WEBSTER C. 
Published: October 2019

Abstract
The Ahm phenotype is distinguished by the absence of H from the cells and anti-H from the serum, the presence of Ax antigen on the cells and A1 and H antigens in the secretions. Similarly, Ohm has no cellular H or serum anti-H and normal quantities of H substances are found in the saliva.
Both phenotypes appear to result from the action of a recessive gene, possibly sex-linked, suppressing H and A1 on the cells but with no effect on the Ax antigen. Ax is considered to be largely independent of the biosynthetic pathway that proposes H substance as a precursor to A and B antigens.
Quantitative hemagglutination studies also disclosed evidence of other genes modifying the quantitative expression of cellular A and H.
Heterozygous Beta-Thalassemia in Association with Hereditary Elliptocytosis: A Family Study
Authors: PERILLIE PASQUALE E. , CHERNOFF AMOZ I. 
Published: October 2019

Abstract
The association of the genes for beta-thalassemia and hereditary elliptocytosis are described in an Italian family. Genetic study of this family indicates that the involved genes are not allelic and are not closely linked. Clinical and laboratory data further suggest that the effects of both genes are summated when present in the same individual.
The Action of Two Sulfhydryl Compounds on Normal Human Red Cells
Authors: SIRCHIA GIROLAMO , FERRONE SOLDANO , MERCURIALI FRANCESCO 
Published: October 2019

Abstract
Treatment of normal human red cells with AET and cysteine, under suitable experimental conditions, modifies them in such a way that their behavior in in vitro hemolysis tests becomes similar to that of the erythrocytes of paroxysmal nocturnal hemoglobinuria.
It is felt that alteration of the red cells is due to the -SH groups possessed by both substances. A possible mechanism of action is hypothesized.
An Electron Microscopic Study of Spleen in Myelofibrosis With Myeloid Metaplasia
Authors: Tavassoli Mehdi , Weiss Leon 
Published: October 2019

Abstract
The ultrastructure of the spleen was studied in four patients with myelofibrosis with myeloid metaplasia (MMM) who underwent splenectomy. The basic structure of the spleen is not altered. Degenerative changes are seen in the white pulp, which appears atrophic. Hemopoietic tissue (erythropoietic and granulopoietic cells, as well as megakaryocytes) is seen in the sinuses, as well as in the cords of the red pulp, but is not seen in the white pulp. Nuclear and cytoplasmic abnormalities are seen in hemopoietic cells. Nuclear changes consist of the nuclear membrane projecting into the cytoplasm and forming nuclear blebs or loops. The nuclear blebs are sometimes connected to the main nuclear body by a stalk containing fibrillar structures. The nuclear loops may be so large as to engulf almost all the cytoplasm. Cytoplasmic changes are degenerative in nature and result in premature destruction followed by phagocytosis. Macrophages are ubiquitous in the red pulp, particularly in association with extracellular reticulum and the basement membranes. They often contain debris of developing hemopoietic cells. These findings support previous studies that indicate that a portion of splenic hemopoiesis in MMM is ineffective.
Toxic effect of puromycin on erythrocyte membranes which is unrelated to inhibition of protein synthesis
Authors: Burka ER , Ballas SK , Sabesin SM 
Published: October 2019

Abstract
Exposure of rabbit or human erythrocytes to concentrations of puromycin as low as 7 x 10(-4)M for 2 hr causes damage to the cell membrane, as evidenced by increased susceptibility of the cells to hyposmotic lysis, increased cell rigidity, and ultrastructural changes consistent with severe membrane damage. Puromycin causes a concentration-dependent internalization of the erythrocyte membrane, resulting in vacuolization of the cells, at concentrations between 7 x 10(-4) M and 10(-2) M. Since the erythrocyte does not synthesize protein, the data indicate that puromycin has a direct toxic effect on erythroid cell membranes which is unrelated to its action in inhibiting the synthesis of protein.
IgG half-molecules: clinical and immunologic features in a patient with plasma cell leukemia
Authors: Spiegelberg HL , Heath VC , Lang JE 
Published: October 2019

Abstract
The clinical manifestations and immunologic features of a patient with plasma cell leukemia who produced k, IgG half-molecules are described. His serum contained both 7S myeloma protein and 4.3S half-molecules, whereas his urine contained predominantly half-molecules. The half- molecules were discovered because the serum and urine formed double precipitin lines when analyzed by commercially available IgG radial immunodiffusion plates that contained antibodies to determinants on both the Fab and Fc fragments. Immunoelectrophoresis also revealed double precipition lines with such antisera. In contrast, when antisera specific for the IgG Fc fragment were used, the serum showed only a single line formed by intact IgG, and the urine failed to react, indicating that the half-molecule was antigenically deficient in the Fc fragment. The half-molecule consisted of one covalently linked heavy and light chain, both having about normal molecular weights, suggesting that they did not have a large deletion which could have caused the half-molecule production. Comparison of the clinical manifestations of the patient with those of four other known patients who produced half- molecules suggested that half-molecule formation is not associated with a distinct clinical syndrome.
Azurophil and specific granules of blood neutrophils in chronic myelogenous leukemia: an ultrastructural and cytochemical analysis
Authors: Ullyot JL , Bainton DF 
Published: October 2019

Abstract
That most patients with chronic myelogenous leukemia (CML) have either very low levels or no leukocyte alkaline phosphatase activity (LAP) is an established fact. In view of our new findings7 that normal mature human polymorphonuclear leukocytes (PMN) contain two types of granules, azurophils (1/3) and specifics (2/3), and that alkaline phosphatase is present only in specific granules, we undertook the present studies to determine whether these neoplastic PMN lack a specific granule population or simply lack the enzyme. The cellular buffy coats of five patients with CML (Ph1 plus, LAP minus) were fixed in glutaraldehyde, incubated for peroxidase to identify the azurophil population, and examined by electron microscopy. It was found that the specific granule population was present in all mature PMN. Counts of both azurophil and specific granules per cell were slightly lower than normal but were within an 80%-90% overlap of the normal range. We therefore conclude that the low level of LAP in patients with CML reflects a deficiency of the enzyme rather than a missing granule population. Although the mature PMN appeared relatively normal (with few exceptions), circulating myeloblasts and promyelocytes revealed several abnormalities, the most notable being the presence of large bundles of cytoplasmic microfilaments. The blood of two patients in the terminal phase of disease was reexamined. Most of their cells were immature, with aberrations similar to those in myeloblasts and promyelocytes in the chronic phase of the disorder. In addition, however, we discovered three adnormal populations of mature PMN: (1) PMN containing both populations of granules but lacking peroxidase, (2) PMN lacking specific granules, and (3) PMN lacking azurophil granules. Our findings emphasize the value of electron microscopy and cytochemistry in detecting abnormalities of maturation in the cytoplasm of leukemic PMN.
Mechanisms for elevated fibrin/fibrinogen degradation products in acute experimental pulmonary embolism
Authors: Cade J , Hirsh J , Regoeczi E 
Published: October 2019

Abstract
The mechanism and significance of elevated levels of serum fibrin degradation products (FDP) in pulmonary embolism were investigated experimentally. Dogs were embolized with autologous blood clot-incorporating canine 125I-fibrin and were infused with either saline, heparin, or streptokinase. Serial measurements were made of total FDP by hemagglutination inhibition assay and of radioactive FDP. After saline, the peak level of total FDP was 323 mug/ml, but radioactive FDP was only 8 mug/ml. After heparin, these values were 44 and 11 mug/ml, respectively, and after streptokinase, 415 and 20 mug/ml. The results suggest that under these experimental conditions the elevated levels of FDP in pulmonary embolism are derived mainly from lysis of fibrin deposited after embolization rather than from lysis of the original embolus. Heparin inhibits both fibrin deposition and elevation of FDP levels after embolism.
Functional and morphologic characteristics of the leukemic cells of a patient with acute monocytic leukemia: correlation with clinical features
Authors: Schiffer CA , Sanel FT , Stechmiller BK , Wiernik PH 
Published: October 2019

Abstract
The clinical course of a patient with acute monocytic leukemia and prominent infiltration of the skin and testes is described. In vitro studies demonstrated that the circulating monocyte precursors were capable of adherence to nylon fibers, and phagocytosis of bacteria and latex particles. In vivo, migration of leukemic cells to skin windows was observed. Extreme nuclear folding, marked surface activity, and morphologic features suggesting nuclear and cytoplasmic maturation were seen by light and electron microscopy. The presence of morphologically and functionally more differentiated monocytic cells may account for the marked tiuuse invasion in this patient and, possibly, in other patients with monocytic leukemia.
Mediterranean macrothrombocytopenia
Authors: Behrens WE 
Published: October 2019

Abstract
Platelet count, platelet size, and circulating platelet biomass concentration estimates made with an erythrocyte-calibrated electronic sizing system on EDTA-anticoagulated blood samples gave population medians and 95% ranges for 145 asymptomatic Mediterranean and 200 healthy Northern European subjects. The Mediterraneans had lower platelet counts [161,000 (89,000–290,000)/mul compared with 219,000 (148,000-323,000)/mul] and higher arithmetic mean volumes [17.8 (10.8- 29.2) cu mum compared with 12.4 (9.9-15.6) cu mum], while the individual lognormal platelet size distribution profiles were comparable [geomatric standard deviations of 1.78 (1.60-1.98) against 1.70 (1.54-1.88)]; and the platelet biomass concentrations, given by count per microliter times mean volume times 10- minus 7 and expressed as a volumetric percentage of whole blood, were almost identical [0.286% (0.216%-0.379%) against 0.272% (0.201%-0.367%)]. Mediterranean macrothrombocytopenia is, therefore, considered a benign morphologic variant that requires differentiation from thrombocytopenias in which the circulating platelet biomass concentration is decreased.
Studies on pure red cell aplasia. VII. Presence of proerythroblasts and response to splenectomy: a case report
Authors: Zaentz DS , Krantz SB , Sears DA 
Published: October 2019

Abstract
An 18-yr-old female with chronic active hepatitis developed a severe anemia due to a lack of red cell production. Her bone marrow showed many large proerythroblasts but an almost complete lack of more mature erythroblasts. Incubation of the marrow cells in a normal medium with erythropoietin concentrate led to increased erythropoiesis as indicated by the development of mature erythroblasts as well as a ninefold increase in hemoglobin synthesis. The patient's plasma was cytotoxic for erythroblasts. Following splenectomy, a remission of the disease occurred. This study indicates that in some cases the anemia associated with abundant marrow proerythroblasts and the absence of mature erythroblasts has the same pathogenesis as pure red cell aplasia and that splenectomy may be beneficial when there is a lack of response to immunosuppressive drugs.
Studies of the human factor VIII/von Willebrand's factor protein. II. Identification and characterization of the von Willebrand protein
Authors: Gralnick HR , Coller BS 
Published: October 2019

Abstract
The purified factor VIII-related protein we have previously characterized from normal cryoprecipitate possesses both procoagulant activity and vWf activity. We have attempted to isolate and characterize this protein from three patients with severe vWd. This protein is absent or markedly diminished in amount in these vWd patients, as judged by gel filtration, polyacrylamide-gel electrophoresis, and immunoprecipitation assays. Likewise, the procoagulant and vWf activities are deficient. As vWf activity is one of the major biologic functions of either the normal or hemophilic factor VIII-related protein, the purified protein should be designated the f VIII/vWf protein.