bluuebunny/crossref_metadata_2025_split huggingface dataset:
Response of Elevated Serum Soluble Interleukin-2 Receptor (sIL-2R) and Overexpression of Glucose-6-Phosphate Dehydrogenase (G6PD) in Patients with Chronic Myelogenous Leukemia Treated with Imatinib Mesylate.
Authors: McPherson Eugene , Shanmughan M. , Huang S.Y. , Kleinfeld J. , Hazel E. , Tassy P. 
Published: April 2020

Abstract
Regulation of intracellular redox potential is important for regulation of cell growth. G6PD functions to catalyze the first step in the pentose phosphate pathway physiologically providing the NADPH required for reductive biosynthesis and detoxification of free-radicals and peroxides in mature red blood cells. We present two cases of patients (pts) with Chronic Myelogenous Leukemia-chronic phase (CML-cp) with significant overexpression of sIL-2R and G6PD. Serum elevated levels of sIL-2R and G6PD correlated to CML stage and response to therapy with imatinib; one male pt and one female pt with white blood cell counts of 80 and 21,000 X 109 per liter and a mean sIL-2R and G6PD levels of 26.975 X 103 pg/ml and 14.10 units/gHb respectively. Both pts had BCR/abl-RT-PCR positive gene rearrangements with b2a2 in peripheral blood and bone marrow. Chromosomal abnormalities of female pt was consistent with CML-cp (t 9; 22) ( q34;q11.2) philadelphia chromosome. Treatment of both pts with imatinib 400 mg orally daily resulted in reduction toward normal levels of sIL-2R and G6PD. Our female pt had to have therapy interrupted due to severe gastrointestinal and myelosuppression with cardiac irritation, edema, headaches and arthralgia. She was changed to 300 mg of imatinib with a proton-pump inhibitor, growth factor G-CSF, and a cox-2 inhibitor with excellent tolerance and response to therapy ( see table I).
Response of sIL-2R and G6PD To Treatment With Imatinib Mesylate
MONTHS LAP-SCORE sIL-2R (pg/ml) CRP (mg/dL) G6PD (units/gHb) LDH (U/L) Lap Score(NL 40-130); sIL-2R (NL 1,770-9,753); G6PD (3.5–5.0) Zero 4 26,975 16.0 11.1 386 Three 12 5,629 2.75 4.1 241 Six 17 12,868 0.75 3.6 266 Twelve 143 6,111 3.75 3.9 203
CONCLUSIONS: Overexpression of sIL-2R and G6PD in CML-cp pts treated with tyrosine kinase inhibitor imatinib mesylate were significantly reduced to levels within normal limits after twelve months of therapy. Peripheral blood sera sIL-2R and erythrocyte G6PD levels in CML-cp pts may be useful clinical and prognostic indicators of leukemic cell burden.
Defective Production of Myeloid Dendritic Cells Results from Skewing of Chronic Myelogenous Leukemia Progenitors.
Authors: Guimond Martin , Boumedine Radia Sidi , Perreault Claude , Roy Denis-Claude 
Published: April 2020

Abstract
The robustness of the immunostimulatory response generated by dendritic cells (DCs) has positioned these cells as central and determining cellular mediators of T cell activation. Their production in sufficient number from hematopoietic precursors is crucial in order to drive immune responses. To determine the capacity of CML clonogenic cells to generate dendritic cells expressing endogenous CML-specific epitopes, we have evaluated the generation of DCs from CD34+ progenitor cells and CD14+ monocytes isolated from patients with CML (n=28). We found that the kinetics of production of DCs, in GM-CSF 800U/ml, TNF-a 50U/ml and IL-4 10U/ml, from CD34+ progenitors of CML patients were significantly delayed in comparison to healthy controls (p&lt;0.05). Even after 20 day-cultures, DC numbers remained decreased (P&lt;0.01). A proliferative defect of CML blasts cannot explain this finding since CD34+ cells divided normally according to total cell culture count and CFSE staining. Flow cytometry analysis of the few DCs produced from CML CD34+ cells showed the same phenotypic characteristics of expression of MHC (class I and II), costimulatory (CD80, CD86) and adhesion molecules (CD11a, CD11b and CD58), as DCs generated from control CD34+ cells, except for late downregulation of CD11a. Normal maturation of DCs from CML CD14+ cells and a sustained proportion of the bcr-abl+ DCs before and after DC expansion excluded a 9:22 translocation-induced differentiation defect. However, retarded down-modulation of the CD34 antigen at the surface of CML blasts, independently of IL-4 receptor synthesis, rather suggested decreased susceptibility of CML progenitors to IL-4 and GM-CSF-mediated DC growth conditions. Indeed, CML progenitors, plated in semi-solid media, showed an important skewing toward more mature progenitors (BFU-E and late CFU-GM) with a significant decrease in immature CFU-GM (&gt; 500 cells) (CML = 29 vs normal = 95 colonies, P&lt;0.001) and CFU-Mix (CML = 0.6 vs normal = 5.6 colonies, P=0.0006). Moreover, the number of DCs obtained after 10 and 15 day-cultures showed a strong correlation with the number of immature CFU-GM and CFU-Mix colonies (R=0.95). Thus, our study identifies a selective impairment in DC production from CD34+ progenitors of CML patients corresponding to a skewing of the progenitor cell compartment toward mature myeloid and/or erythroid progenitors. The lack of DCs derived from leukemia progenitors may explain the immunologic escape of CML clonogenic cells and provides clues to enhance their immune recognition.
Anti-Erythroblast Antibodies and Defective Apoptosis in Bone Marrow of Early Myelodysplastic Syndrome Patients.
Authors: Zaninoni Anna , Imperiali Francesca G. , Fermo Elisa , Zanella Alberto , Barcellini Wilma 
Published: April 2020

Abstract
Autoimmune phenomena, particularly directed against RBC, and alteration of apoptosis have been reported in MDS. We recently described a new method for the detection of anti-RBC antibodies in mitogen-stimulated whole blood cultures, named mitogen-stimulated-DAT (MS-DAT), which is able to disclose a latent anti-RBC autoimmunity in different diseases (autoimmune hemolytic anemia in clinical remission and in B-CLL). We investigated MS-DAT positivity and apoptosis in peripheral blood and bone marrow cultures from 14 patients with refractory anemia (RA) and RA with ringed sideroblasts (RARS), compared with controls (healthy volunteers and miscellaneous haematological conditions). MS-DAT was performed by stimulating whole blood and marrow cultures with PMA, and anti-RBC or anti-erythroblast antibodies were detected by competitive solid phase ELISA. As apoptotic markers we evaluated NF-kB and Caspase-3 activity by ELISA and enzymatic assay, respectively. As shown in table, the amount of anti-erythroblast antibodies was significantly greater in BM cultures of MDS versus controls, and the test was clearly positive in 8/14 patients (not shown). The anti-apoptotic marker NF-kB was significantly increased in MDS versus controls, and consistently, caspase-3 activity decreased, although not significantly. On the contrary, PB of MDS displayed no MS-DAT positivity and no significant alterations of apoptotic and anti-apoptotic markers investigated (not shown). These findings suggest the existence of an anti-erythroblast autoimmunity in bone marrow of early MDS patients. This could be related to the observed defective apoptosis, which in turn determines survival of auto-reactive marrow effectors.
MDS Controls Medium PMA Medium PMA *denotes statistical significance versus controls. Values are mean±SE Anti-erythroblasts (pg/ml) 407±116* 487±146* 76±15 99±20 NF-kB (OD units) 294±50* 358±83 59±20 67±21 Caspase-3 (OD units) 132±24 145±26 209±53 186±46
Arsenic Trioxide (Trisenox®) with/without Thalidomide in Patients with Myelodysplastic Syndromes (MDS) Produces Hematologic Improvement (HI).
Authors: Raza Azra , Lisak Laurie , Billmeier Jennifer , Akbar Samreen , Washeed Khalid , Mumtaz Mohammad , Reddy Poluru , Galili Naomi 
Published: April 2020

Abstract
In a previous clinical trial, we have shown that 7/28 MDS patients, belonging to IPSS intermediate and high risk categories, responded to a combination of Trisenox® and thalidomide including a complete hematologic and cytogenetic remission. Two trilineage responses were seen in patients with inv(3) abnormality. It was not clear whether the responses were due to the combination or to either drug alone. In the present study, we treated 30 MDS patients with Trisenox® (5 days of loading dose at 0.25mg/kg IV over 2 hours followed by twice weekly dose) for 6 months followed by the addition of thalidomide (100mg po qday x 3 months). The Median age was 71 years (19 males, 11 females). FAB types: RA 3 patients, RARS 2, RAEB 14, RAEB-t 8, CMMoL 2, Unclassified 1. IPSS: Low 0 patients, Int-1 10, Int-2 7, High 13. Two, 1,1 and 4 patients had abnormalities affecting chromosomes 5, 7, 8, and 20, while 12 patients showed a complex karyotype. Therapy was fairly well tolerated and median number of cycles was 3. Five patients showed a variety of hematologic responses as judged by the IWG criteria (1 trilineage, 1 cytogenetic and change in FAB type due to decrease in blasts, 1 ANC and reduction in blasts, and 2 with 50% reduction in blasts). Among the responders, 1 had 47 XX, +8(16 metaphases), del(X)(q22q25),del(3)(q25q27)(4 metaphases), 3 had a normal karyotype, and 1 had del(20q). Three of the partial responders were started on thalidomide, but all stopped within 2 months. Following response, the first patient showed disappearance of the clone bearing the chromosome 3 abnormality, confirming the sensitivity of these cells to Trisenox® as reported in our previous trial. Interestingly, 3/5 responders showed an increase in WBC/ANC and 1 in platelets as well (12, 22 and 90,000/ul), without any evidence of a differentiation syndrome. One also had an increase in platelets from ~50,000/ul to 966,000/ul. Blasts were 11, 24 and 28% in these 3 patients prior to therapy and decreased to 4, 6 and 24% respectively after treatment. It was concluded that the twice-daily dose of arsenic trioxide was well tolerated, and some patients converted their disease to a more myeloproliferative type picture.
Myelodysplastic Syndrome Due to Somatic GATA1 Mutation.
Authors: Freson Kathleen , Vyas Paresh , Thys Chantal , Wittevrongel Christine , De Vos Rita , Van Geet Chris 
Published: April 2020

Abstract
Inappropriate hematopoietic differentiation resulting in trilineage dysplasia is a diagnostic hallmark of myelodysplastic syndrome (MDS). Understanding the molecular basis of MDS will not only shed insight into this common hematological disease, but also Acute Myeloid Leukemia (as MDS often progresses to AML) and normal hematopoiesis. The genetic basis of MDS is unclear and in particular the role of deregulated transcription factor activity, which is often seen in AML, has not been clearly defined. For the first time we describe a novel somatic GATA1 mutation in a 13-year-old boy with MDS who has 10-year history of anemia, neutropenia, moderate thrombocytopenia, bone pain and hepatomegaly. Bone marrow biopsy demonstrated trilineage dysplasia with a normal karyotype of bone marrow mononuclear cells. Sequence analysis showed an A to G mutation in the X-linked GATA1 gene at residue 598 in exon 4 in platelets and bone marrow mononuclear cell cDNA. The mutation was also detected in genomic DNA from purified myeloid progenitors but not peripheral blood leucocytes. This discrepancy may be due to selection of peripheral blood leucocytes that do not carry the GATA1 mutation. The mutation was also not seen in skin fibroblasts. The predicted amino acid substitution E200G is located in a highly conserved residue at the beginning of the N-terminal zinc finger (Nf). This did not perturb DNA binding to GATA sites by EMSA analysis nor reduce interaction with FOG1. Importantly, immunoblot analysis of the patient’s platelets showed strongly reduced protein levels of GATA1, normal FOG1 and increased RUNX1. The index case had an increased Ivy bleeding time (&gt;15 min) and a significant prolongation of the PFA-100 occlusion time (collagen/ADP and collagen/epinephrine). Platelet ATP secretion and platelet aggregation (epinephrine, ADP and U46) were decreased compared to control platelets. In contrast to patients with an inherited GATA1 mutation, the platelet phenotype in the MDS patient is completely different. Platelets from the patient are smaller in size (MPV 8.6fL) and electron microscopy revealed a markedly reduced number of dense granules. His platelets have a normal GPIbα expression and normal ristocetin-induced platelet agglutination. The previously described patients with inherited Nf GATA1 mutations (D218G GATA1 Blood,2001,98,85) have giant platelets with characteristic membrane complexes and reduced GPIbα expression with abnormal ristocetin-induced platelet agglutination. Further study of the index patient will provide important detailed insight into GATA1 function and help unravel how perturbed activity of key myeloid transcription factors results in MDS.
Evidence for T-Cell Involvement in MDS: Similar Patterns of Hypermethylation of Key Genes in Purified CD34+ and CD3+ Cell Fractions in an RAEB Patient.
Authors: Aggerholm Anni , Rethmeier Anita , Guldberg Per , Carlsen Ingrid , Brændstrup Karin , Hokland Peter 
Published: April 2020

Abstract
Aims: Myelodysplastic syndromes (MDS) constitute a heterogeneous group of disorders with hematopoiesis in disarray and with preponderance to transformation to AML. In contrast to the situation in de novo AML patients, the hematopoiesis in MDS patients is often though to encompass most cell lineages with few non-malignant cells in the bone marrow due to displacement by the MDS clone. While the involvement of the myeloid sublineages has been relatively easy to verify in semi-solid CFU assays, that of the lymphoid lineages has required advanced flow sorting techniques in combination with FISH assays in the minority of MDS patients with a well-known genetic aberration such as 5q-, -7 or +8. Moreover, the latter studies have usually been restricted to the description of the involvement of the B-cell lineage. Transcriptional silencing of tumor suppressor genes by promoter hypermethylation is associated with hematological malignancy, including MDS. In a patient with a very immature MDS that was found to be hypermethylated in the p15, HIC, E-cadherin, and Estrogen receptor genes, we wanted to elucidate the methylation status in both myeloid and lymphoid cells.
Material and methods: Mononuclear cells from a 69-year-old female MDS patient with RAEB was analyzed. Using magnetic cell sorting, CD34 and CD3 positive cells were isolated from BM-MNC and PB-MNC, respectively. The purity of the isolated cell fractions was determined by flow cytometry (CD34+: 95% and CD3+: 84%). DNA isolated from the cells was treated with sodium bisulfite and analyzed for promoter hypermethylation in the p15, HIC, E-cadherin, and Estrogen receptor genes by means of Bisulfite-Denaturing Gradient Gel Electrophoresis (Bisulfite-DGGE).
Results: All cell fractions were found to be hypermethylated in the four genes analyzed. Since the Bisulfite-DGGE allows for the detection of heterogeneous methylation patterns, we were able to compare these patterns. Similar Bisulfite-DGGE band patterns were observed in total BM-MNC, total PB-MNC, CD34+ cells and CD3+ cells.
Conclusion: Because the methylation band patterns were the same in all cell fractions, it seems unlikely that methylation has occurred independently in progenitors committed for myeloid and lymphoid maturation, respectively. We therefore conclude that promoter hypermethylation in this patient has occurred in a stem cell with potential for both myeloid and lymphoid maturation. This methodology should provide an easy way to assess the extent of clonality of hematopoiesis in MDS patients.
Clinical Trial of Paricalcitol in Myelodysplastic Syndrome.
Authors: Koeffler H. Phillip , O’Kelly James , Aslanian Noune ,   The Southern California Leukemia Group
Published: April 2020

Abstract
Myelodysplastic syndrome is often a pernicious disorder associated with pancytopenia in the elderly. Therapeutic approaches need to balance their toxicities versus the side-effects of the disease. 1,25(OH)2-vitamin-D3 inhibits proliferation and induces differentiation of leukemic cells in vitro. Small clinical trials have shown slight efficacy in MDS. Hypercalcemia prevents the administration of doses of this seco-steroid, which have been shown to be effective in vitro. This has provided a stimulus to identify vitamin D analogs that have anti-leukemic activity with minimal hypercalcemic effects. Paricalcitol (19-nor-1,25(OH)2D2, Zemplar) has been approved by the FDA for the treatment of secondary hyperparathyroidism; the drug is unique because it has little hypercalcemic potential; but in vitro, it has strong antileukemic effects. We conducted a clinical trial of oral paricalcitol to twelve MDS patients whose disease varied between an IPSS of low to high. Therapy began at 8 μg per day and increased at two week intervals until serum calcium was slightly above normal level; at which point, dose was decreased by 4-8 μg qd. The amount of paricalcitol taken varied between 8 μg qod to 54 μg qd (average 16 μg qd). We confirmed that the drug was having biologic activity in vivo by examining a target of the activated vitamin D3 receptor, 1,25-(OH)2-vitamin-D3-24(OH)ase mRNA. Each patient had prominent induction of this transcript in his or her white blood cells. Furthermore, in selected patients serum paricalcitol was measured and confirmed to be prominently present. The drug was well tolerated in all patients. Two of the 12 patients showed a clinical response. One patient’s platelet counts rose from 50,000 to 120,000/ul blood over 5 weeks; however, the patient succumbed to a fatal fungal infection. The second patient responded by a decrease in RBC transfusions associated with a rise in his hemoglobin, which lasted for about 5 months. Eventually, his hemoglobin began to fall, and erythropoietin therapy was substituted for paricalcitol. In summary, high doses of paricalcitol were well tolerated in all patients. Two patients had a partial clinical response. In general, paricalcitol given as a single agent to individuals with MDS is not therapeutically very efficacious; further trials should examine it in combination with other approaches.
Phase II Study of Gemtuzumab Ozogamycin (GO) and Cytarabine (ARA-C) in Patients with High Risk MDS and AML..
Authors: Kang Peter , Seiter Karen , Liu Delong , Arshad Muhammad , Qureshi Anila , Nelson John , Ahmed Tauseef 
Published: April 2020

Abstract
To evaluate the efficacy of GO + ara-c in high risk pts, we treated 22 pts with MDS (10) and AML (12) with cytarabine 100 mg/m2/d x 7 d and GO 9 mg/m2 x 1 on d 4. Pts with MDS were eligible if they had [1] RAEB-1 and either hgb &lt; 8 gm/dl, platelet &lt; 50,000/mm3, neutrophils &lt; 1000/mm3, or cytogenetics other than 5q-, 20q-, -y, or normal, [2] RAEB-2, or [3] CMML. Pts with AML (newly diagnosed or relapsed) were eligible if they were ineligible for anthracycline-based therapy (poor performance status: 2 pts; low ejection fraction or high cumulative dose of anthracyclines: 6 pts, both reasons: 4 pts). The median age was 66, M:12, F:10. Diagnoses: RAEB-1: 4, RAEB-2: 5, CMML: 1, AML, newly dx’d: 7, AML relapsed: 5. Cytogenetics were high risk: 10, intermediate risk: 11 pts, low risk: 1 pt. Overall, 18% had a complete response (CR) after one cycle of therapy. Three pts (14%) had a partial response (PR), of which one had a CR after a second course of therapy. Of the pts with AML: CR: 2/12, PR: 2/12, Failure (F): 5/12, Toxic Death (TD): 3/12. For pts with MDS: CR: 2/10, PR: 1/10, F: 5/10, TD: 2/10. Toxicities included neutropenic fever/sepsis, mucositis, diarrhea, increased LFTs, hemorrhage. One pt with a history of ABVD and RT to chest for HD developed direct pulmonary toxicity due to chemotherapy (diffuse pulmonary infiltrates, biopsy proven toxic lung damage). Although overall response rate is modest, some pts had remarkable responses: One pt with RAEB-1, transfusion dependent and multiple high risk cytogenetics (−5, −7, multiple others) remains in CR (including cytogenetic CR) 7 months post treatment. A second pt with RAEB-1, transfusion dependent and multiple high risk cytogenetics (−5, −7, multiple others) had a PR after one course, but was unable to receive further chemotherapy due to toxicity. The latter pts suggest that this regimen should be studied further in pts with MDS, poor risk cytogenetics and low blast counts.
Acute Myeloid Leukemia (AML) - Type Chemotherapy for Newly Diagnosed Children with Myelodysplastic Syndrome (MDS): A Japanese Childhood MDS Study Group Trial MDS99.
Authors: Ohtsuka Yoshitoshi , Manabe Atsushi , Okamura Jun , Kojima Seiji , Ohara Akira , Tuchida Masahiro , Ikuta Koichiro , Hibi Shigeyoshi , Kawa Keisei , Yabe Miharu , Watanabe Arata , Ueda Kazuhiro , Nakazawa Shinpei , Miyazaki Sumio , Nakahata Tatsutoshi 
Published: April 2020

Abstract
Background The role of intensive chemotherapy in treatment of childhood MDS has not been clarified yet. We conducted a prospective trial which employed intensive AML-type chemotherapy for children with de novo MDS.
Methods Fifteen children aged 1 to 15 years who met diagnostic criteria of the FAB refractory anemia with excess of blasts (RAEB) with more than 10% of blasts in the bone marrow (BM) (RAEB-II) and RAEB in transformation (RAEBT) were prospectively enrolled in the study. Abnormal karyotype was documented in 11 patients including 3 with monosomy 7, 2 with complex karyotype, 1 with trisomy 8. Induction therapy consisted of etoposide (150mg/m2, on days 1–5), cytarabine (200mg/m2/12hr, on days 6–12), and mitoxantrone (5mg/m2, on days 6–10) in all but 1 patient, who received another regimen of AML induction therapy. The use of granulocyte-colony stimulating factor was allowed. Allogeneic stem cell transplantation (SCT) was scheduled after remission induction therapy. The median follow-up for 13 surviving patients was 685 days (58 to 1,476 days).
Findings Eleven patients (73%) including 3 with monosomy 7 achieved a complete remission after induction therapy at a median of 40 days (31 to 61 days). Remission was not obtained in the other 4 patients.
There was no significant difference in the frequency and severity of toxicity between in patients with RAEB-II/RAEBT and in those with de novo AML. Allogeneic SCT was performed in 13 patients including 9 in the remission at a median of 4 months (2 to 6 months) after the beginning of the therapy. None of nine patients who underwent SCT in the remission relapsed. Although two patients died of the complications of SCT. Overall survival for all the 15 patients at 2 years was 66.8 ± 14.1% (s.e.).
Interpretation AML-type induction therapy appears to be safe and effective for children with RAEB with more than 10% of blasts in the BM and RAEBT.
Figure Figure