bluuebunny/crossref_metadata_2025_split huggingface dataset:
Therapy Related Acute Myelogenous Leukemia and Myelodysplastic Syndrome in Patients with Acute Lymphoblastic Leukemia Treated with the Hyper-CVAD Regimen.
Authors: Verma Dushyant , Thomas Deborah , O’Brien Susan , Faderl Stefan , Koller Charles , Pierce Sherry , Estey Elihu , Garcia-Manero Guillermo , Cortes Jorge , Kantarjian Hagop , Ravandi Farhad 
Published: October 2019

Abstract
Secondary malignancies including myeloid neoplasms occur infrequently in patients with acute lymphoblastic leukemia (ALL). This has been well documented in the pediatric population but not for the adult patients. We have reviewed retrospectively 641 patients with de novo ALL, treated with the hyper-CVAD regimen or its variants, at M D Anderson Cancer Center from 1992 to 2007. Fourteen patients (2.18%, 7 female, 7 male) developed secondary acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS). Six patients had AML and 8 MDS. Median age at the time of ALL diagnosis was 52 years (range, 23 – 66). Cytogenetics at ALL diagnosis was diploid in 10, pseudo-diploid with −2 in 1, t(9;22) in 1, and unavailable in 2 patients. Frontline therapy included hyper-CVAD in 7, hyper-CVAD with rituximab in 6, and hyper-CVAD with imatinib in 1 patient. Karyotype at the time of AML/MDS diagnosis was −5, −7 in 8 patients, diploid in 1, miscellaneous in 1, inv(11) in 1, t(4;11) in 1, and unavailable in 2. Secondary AML/MDS developed at a median of 31 months (range, 11 – 74) after the start of ALL therapy. Treatment for the secondary AML and MDS was varied and included cytarabine plus anthracycline based regimens for AML and high risk MDS. One patient with MDS received arsenic trioxide, 1 clofarabine, and 1 decitabine. The response rate to treatment for AML/MDS was complete remission (CR) in 2, partial remission in 6 and no response in 6 patients. Five patients (all MDS) underwent an allogeneic stem cell transplant and all but one died at a median of 3 months (range, 0.5 – 11) after the transplant. One patient is alive and in CR 14 months after a haplo-identical sibling transplant; 2 other patients are alive 3.5 and 4 months after the diagnosis of MDS. The median overall survival after the diagnosis of secondary AML and MDS is 8.3 months (range 3.5+ to 18.5+). We conclude that secondary AML and MDS occur infrequently (2.18%) in adult patients with de novo ALL treated with the hyper-CVAD regimens and response to their subsequent therapy is poor.
Evaluation of Clinical Judgement at Initiation of AML-Therapy in Elderly Patients - A Prospective Randomized Trial.
Authors: Schuler Ulrich S. , Hanel Mathias , Bodenstein Heinrich , Einsele Hermann , Pflueger Karl-Heinz , Schmitz Norbert , Wagner Thomas , Wandt Hannes , Herbst Regina , Kaiser Ulrich , Ehninger Gerhard 
Published: October 2019

Abstract
Treatment decisions for AML in elderly patients are based on a more individualized approach than in younger patients. Increasing age is associated with both decreasing efficacy of conventional therapy, increasing influence of comorbidity and functional impairment on the overall outcome. In a prospective trial we tried to answer two questions. (A) Comparison of DA and I-MA -Induction (B) prospective evaluation of the clinical judgement of the haematologist concerning the overall prognosis of the patient. Physicians requesting the randomization by FAX had to give their impression on a 5 point Likert-scale, whether they regarded the overall prognosis of the patient as inferior, comparable or superior to the respective age group, prior to the first dose of chemotherapy. In part (A) Patients >60 years were randomized between DA (Daunorubicin 45mg/m2 d3−d5 +Ara-C 100mg/m2 d1–d7) and I-MA- induction therapy. In a single arm-study, it had been claimed by others [ASH 2002 abstract 1337] that I-MA (Mitoxantrone 10 mg/m2 d1-3, Ara-C 1 g/m2 2x/d on d1,d3,d5, d7) in patients >60yrs results in high CR-Rates of 73% in de novo and in 59% in secondary AML. Given the expectation of a considerable superiority, several interim analyses were planned, in order to stop the trial early, if I-MA should be shown to improve CR-rates or survival. The most recent analysis is based on 206 patients (more than 60 days on study and evaluable for CR). Concerning part (A) neither CR-rates nor survival differed significantly (overall CR-rate 50%, trend favouring I-MA, survival trend after 1 year favouring DA). In part (B) physicians avoided extremes of the Likert scale. Only in the minority of cases cytogenetic data were available at the time of randomization, but judgement proved to be of value even if this variable was included in the Cox-model. This data show for the first time that clinical judgement (without formal comorbidity scoring or functional assessment) is of value in predicting the prognosis of elderly AML-patients treated uniformly within a randomized trial.
Physician estimate of prognosis Frequency Average Age (median) in years Median Survival (months) p-value (log-rank) inferior 23% 69,7 (69) 4.9 comparable 62.7% 68,7 (69) 7.4 0.124 superior 14.3% 68,5 (68,3) 10.1 0,013
Untreated Patients with Acute Myeloid Leukemia, Age 50–59 Years and Performance Status 2 Should Be as Eligible for Targeted Therapy as Older Patients.
Authors: Tsimberidou Apostolia M. , Kantarjian Hagop M. , Faderl Stefan , Pierce Sherry , Freireich Emil J. , Estey Elihu 
Published: October 2019

Abstract
Background: The early mortality rates in older patients (generally defined as those > 60 years) following standard therapy for acute myeloid leukemia (AML), has spurred numerous trials of “targeted” treatments, typically limited to this age group. Here we examine whether younger patients with Zubrod performance status (PS) 2 might also be candidates for these therapies.
Patients and Methods: We reviewed the records of 1841 patients 40 years or older with newly diagnosed AML (no acute promyelocytic leukemia) who received cytarabine-containing therapy at M. D. Anderson from 1980 to 2007. We chose patients with the following pretreatment characteristics because they are conventional criteria for entry onto trials of new therapies: PS 0–2, bilirubin < 2 mg/dL, and creatinine < 2 mg/dL. We calculated death rates by age and PS at 28 and 42 days after initiation of induction therapy.
Results: Induction death rates in patients with AML by age and performance status The 28-day death rates in patients age 50–59 years with PS 2 were similar to those in patients ≥ 60 years with PS 0–1, and the 42-day death rates in the patients age 50–59 years with PS 2 were similar to those in patients age 60–79 with PS 0–1.
Conclusion: Because of the high death rates following AML therapy in patients age 50–59 with PS 2, these patients should be eligible for targeted treatments now limited to older patients.
Age, yrs Performance Status No. of Patients Dead by day 28, % Dead by day 42 % 40–49 0–1 288 7 9 40–49 2 38 5 5 50–59 0–1 405 4 6 50–59 2 85 14 15 60–69 0–1 423 8 11 60–69 2 111 17 17 70–79 0–1 301 12 16 70–79 2 124 23 33 ≥80 0–1 45 13 20 ≥ 80 2 21 38 43
Mirasol™ Pathogen Reduction of Packed Red Blood Cells (PRBCs) and Apheresis Platelet (Aplt) Concentrates Decreases Neutrophil Priming Activity Generated during Storage.
Authors: Ambruso Daniel R. , Thurman Gail , Marschner Susanne , Goodrich Ray 
Published: October 2019

Abstract
Introduction: During storage of cell containing components including PRBCs and Aplts, biologically active compounds such as lysophosphatidylcholine and other lipids are generated. Identified by their ability to enhance the fMLP stimulated respiratory burst in neutrophils, these biologic response modifiers (BRMs) have been implicated in the pathogenesis of transfusion related acute lung injury (TRALI). The Mirasol pathogen reduction system is a process that uses riboflavin and UV light to modify nucleic acids, reduce infectious pathogen load and inactivate white blood cells in blood components. An additional effect of the Mirasol in PRBCs and Aplts is a decrease in priming activity accumulated during storage.
Methods: PRBCs were produced by standard technique from whole blood donation. PRBCs were treated with Mirasol (8) and stored; untreated, washed and stored in AS-3 additive solution (2); or produced untreated and stored in AS-3 (6). For platelets collected on Trima, one set of products was treated with Mirasol procedure on day 0. Another set was exposed to 25Gy of gamma irradiation. The control group was untreated and stored under standard conditions. Samples were removed on day 0 and 43 (PRBCs) and day 0, 5, 7 (Aplts); cells removed from residual supernatant/plasma by centrifugation and frozen at -70°C. Samples (10% by volume) were assayed to measure the ability to enhance the fMLP stimulated superoxide anion production (O2−) by peripheral blood neutrophils. O2− was measured as SOD inhibitable cytochrome c reduction and expressed as a ratio of the response to plasma followed by fMLP compared to fMLP alone. Priming by platelet activating factor (PAF) was a positive control. Priming is defined as >1.5 fold increase in O2− over the results for fMLP alone.
Results: Samples from Mirasol treated PRBCs show no enhancement of fMLP stimulated O2− production either at day 0 or after 43 days of storage (Top figure). Washed controls exhibit a similar pattern. Unwashed controls demonstrate a small amount of priming on day 0 which further increased on day 43. For Aplts (Bottom figure), day 0 samples exhibited minimal priming. For Mirasol treated products, no changes were seen on days 5 and 7. In contrast, both gamma irradiated and untreated Aplts showed an increase comparable to that seen with PAF.
Conclusion: Treatment of PRBCs and Aplts with Mirasol reduced the generation of priming activity normally developed during storage, possibly representing a decrease in production of BRMs including priming lipids. Mirasol treatment of cell containing components may reduce one class of etiologic agents associated with TRALI and may be a potential approach to reduce risk for this adverse event of transfusion.
Figure Figure
Deficiency of the VWF-Cleaving Protease ADAMTS13 Results in Increased Leukocyte Rolling and Adhesion in Mice.
Authors: Chauhan Anil K. , Kiucka Janka , Brill Alexander , Walsh Meghan T. , Wagner Denisa D. 
Published: October 2019

Abstract
von Willebrand factor (VWF) is synthesized in megakaryocytes and endothelial cells and stored in a-granules and Weibel-Palade bodies, respectively. VWF levels are elevated in both chronic and acute inflammation. ADAMTS13 (A D isintegrin-like A nd M etalloprotease with T hrombo s pondin type I repeats-13) is a metalloprotease that cleaves ultra large von Willebrand factor (ULVWF) multimers quickly after its release from endothelium. Recent studies have found that VWF promotes leukocyte adhesion in vitro and that ADAMTS13 activity is reduced in inflammation and sepsis. We hypothesized that by cleaving ULVWF multimers, ADAMTS13 not only inhibits thrombosis, but also attenuates leukocyte rolling and adhesion. Using intravital microscopy, we found more leukocyte rolling/min on the unstimulated veins in Adamts13-/- mice (Mean ± SE: 98 ± 16) compared to WT (Mean ± SE: 35 ± 6, P<0.001), n=18–20 from 10–11 mice per group. This process was dependent on VWF because the number of leukocytes rolling in Adamts13-/-/Vwf-/- veins was similar to that in Vwf-/-. Significantly increased soluble P-selectin and VWF concentrations were found in the plasma of Adamts13-/- compared to WT mice as quantitated by ELISA. In addition, endothelial P-selectin surface expression was increased in Adamts13-/- mice compared to WT. These results suggest elevated release of Weibel-Palade bodies in Adamts13-/- mice. Notably, circulating platelets were not activated in the absence of ADAMTS13. Upon stimulation of the mesentery with histamine, leukocyte rolling was slower in Adamts13-/- veins compared to WT. Furthermore, upon stimulation with the inflammatory cytokine TNF-alpha (i.v) 3.5 h prior to surgery, the number of leukocytes adhering/250 um was significantly increased in microvenules (diameter of 25–30 um) of Adamts13-/- mice (Mean ± SD: 21 ± 6) compared to WT (Mean ± SD: 12 ± 5, P<0.001), n=10–11 mice per group. This firm adhesion was also dependent on VWF because the number of adherent leukocytes in veins of Adamts13-/-/Vwf-/- was similar to Vwf-/-. Our studies indicate a crucial role for ADAMTS13 in preventing excessive spontaneous Weibel-Palade secretion and in attenuating leukocyte rolling and adhesion to ultra large VWF presented by endothelial cells during inflammation.
Emergency Blood Supply Planning: A Statewide Prospective Audit To Determine the Potential Benefits of Triaging Red Cells during a Critical Shortage.
Authors: Shortt Jake , Polizzotto Mark N. , Waters Neil , Jones David , Borosak Marija , Moran Martine , Devine Alexandra , Jolley Damien J. , Wood Erica M. 
Published: October 2019

Abstract
Careful planning is critical to ensure blood availability during times of reduced supply and/or increased demand, such as infectious pandemic, act of terrorism or natural disaster. Possible strategies include triaging of supply to prioritize support where transfusion cannot be deferred. However, few data concerning urgency of transfusion are available to inform planning. We designed a random sample survey to assess urgency of clinical need, and hence potential utility of triaging red cells (RC) in an emergency through restricting use only to urgent indications, for a regional population of approximately 5 million. An audit based on random sampling of units at point of distribution was used to assess state-wide RC use over time, and capture data in proportion to actual usage over both rural and metropolitan centers. Randomly selected RC units were tagged with a case-report form during production. Tagged units were distributed to hospital laboratories with routine supply. At time of issue for transfusion, the institutional laboratory completed and returned case report forms from the tagged units. Information regarding recipient demographics, indication for transfusion, urgency of supply, and (where issued to support surgery) urgency of surgery were obtained. Following an initial pilot study to refine the model, approximately 1000 tagged RC units (46% group O, 36% A, 13% B, and 4% AB; RhD positive 85% / negative 15%) of a planned 5000 total have been introduced to the state inventory. Three percent of units were not transfused. Major clinical categories of use included hematology (17% of overall use), gastroenterology (11%), orthopedic surgery (9%), non-hematological oncology (6%), gastrointestinal surgery (6%), cardiothoracic surgery (5%), obstetrics/gynecology (5%), urology (3%), trauma (3%) and pediatrics (2%); miscellaneous indications and anemia not otherwise specified constituted 10% and 22% of transfusions respectively. 18% of units were used in acute transfusion episodes (needed within 1h), 43% for urgent indications (1–24h), 33% semi-urgent (24h - 1 week) and 4% non-urgent. Of the 34% units allocated to support perioperative bleeding; only a quarter of procedures were elective. In 15% of cases the urgency of surgery was not stated. Thus, reporting institutions indicated that only 38% transfused units could have been deferred for more than 24h, and only 9% of total RCs were allocated to support potentially deferrable elective surgery. These early results suggest that triaging of RC supply in an acute shortage would only have a very short term impact on actual RC use, as the majority of RC use is already relatively urgent. Additional strategies for emergency blood contingency planning are required to meet priority clinical needs.
Polymorphic Variation at the STAT5 Locus Is Associated with the Response of CML Patients to Interferon Alpha.
Authors: Kreil Sebastian , Waghorn Katherine , Hehlmann Rudiger , Reiter Andreas , Hochhaus Andreas , Cross Nicholas C.P. 
Published: October 2019

Abstract
Interferon alpha (IFN) induces complete hematologic remission in 70% to 80% of patients with CML in early chronic phase, with up to 8–30% of cases achieving a complete cytogenetic response (CCR). Although patient responses correlate with Hasford and Sokal risk scores, the molecular basis for this heterogeneity remains poorly understood. We hypothesized that polymorphic differences in the IFN signal transduction cascade might account for different patient responses. IFN binds the heterodimeric type I interferon receptor, the two subunits of which are encoded by IFNAR1 and IFNAR2. Binding activates the JAK1 and TYK2 non-receptor tyrosine kinases, which phosphorylate and activate STAT proteins. We studied 187 cases treated with IFN based regimens as part of the German CML studies I-III. Of these, 105 were defined as non-responders (no cytogenetic response) and 82 as responders (achievement of <=34% Philadelphia-chromosome positive metaphases) after a median treatment duration of 23 and 40 months, respectively. There was no significant difference in the incidence of der(9) deletions between the two groups. We genotyped 14 single nucleotide polymorphisms (SNPs) within or close to the genes encoding IFNAR1, IFNAR2, JAK1, TYK2, STAT1, STAT3 and STAT5a/b and compared allele frequencies between responders and non-responders. Significant differences were found for two SNPs at the STAT5a and STAT5b loci. For rs16967611 the minor allele frequency (maf) was 0.34 for non-responders and 0.28 for responders (P=0.21; chi-squared test) and for rs6503691 the maf was 0.16 for non-responders and 0.07 for responders (P=0.005). The latter SNP remained significant when corrected for multiple testing. Three other SNPs at STAT5a/b (rs9900213, rs17500235 and rs17591972) were also analyzed and yielded P values of 0.87, 0.01 and 0.15 respectively. STAT5a, STAT5b and STAT3 are tightly linked at 17q21 and show strong linkage disequilibrium according to HapMap data. To determine if the genotype at rs6503691 is related to gene expression levels, we measured STAT5a, STAT5b and STAT3 mRNA in 214 pretreatment CML patients by real time quantitative PCR. There was no difference in the median normlised expression of STAT3 and STAT5a in cases with a c/c genotype compared to those with c/t or t/t, however for STAT5b the expression level was higher in cases with a c/c genotype (P=0.02). We conclude that rs6503691, located within STAT5b intron 1, is associated with the expression level of STAT5b and response of CML patients to IFN.
The Expression of SALL4, a Newly Identified Stem Cell Factor, Is Correlated with Chronic Myeloid Leukemia (CML) Disease Progression.
Authors: Ma Yupo , Yang Jianchang , Kong Nikki , Amin Hesham M. , Chai Li 
Published: October 2019

Abstract
The homeotic gene, SALL4, plays an essential role in the maintenance of embryonic stem cell pluripotent and self-renewal properties by interacting with two other key regulators in ESCs, Nanog and Oct4. Previously, we have demonstrated that SALL4 contributes to acute myeloid leukemia (AML) development in a murine model. Also, Bmi-1, a key regulator in leukemic stem cells (LSCs), is a direct target of SALL4. In this study, through immunohistochemistry and fluorescent activated cell sorting (FACS) analysis, we demonstrated that the expression level of the SALL4 protein correlated well with disease progression in CML. There was no SALL4 positive population detectable in normal whole bone marrow samples or chronic phase CML samples. A distinguish SALL4 positive population was present in accelerated and blastic phases of CML marrows, and overlapped with a subset of CD34+ population. This finding is particular of interesting since committed Granulocyte-Macrophage Progenitors (GMPs) are CD34+/CD38+ cells and have been proposed to be candidates for LSCs in the AML to CML transformation. Decreasing SALL4 expression in a CML cell line (KBM5) down regulated Bmi-1 expression, which resulted in increased caspase-3 activity, induced cell-cycle arrest, and decreased cell proliferation. Furthermore, restoration of Bmi-1 expression rescued apoptosis, increased cell proliferation, and promoted cell-cycle progression. Our data have extended our understanding on the stem cell factor SALL4 in CML transformation and its role in the pathogenesis of CML disease progression. SALL4 can also potentially be used as a novel diagnostic marker for CML transformation.
A Prospective Gene Expression Profiling Study for Prediction of Cytogenetic Response in Early and Late Chronic Phase CML.
Authors: Wolf Dominik , Schmidt Stefan U. , Fong Dominik , Wrulich Oliver , Lion Thomas , Überall Florian , Petzer Andreas , Gastl Günther 
Published: October 2019

Abstract
Gene expression profiling has proven useful for identification of gene sets predicting response and/or prognosis in various hematological malignancies. So far expression profiling studies in CML predicting response to imatinib therapy suffered from major flaws, as previous retrospective studies relied on various technical platforms using rather small patient populations. Here, we present the interim results of an expression profiling study performed within a prospective multicenter CML trial of the Central European Leukemia Study Group(CELSG) comparing standard (SD) with high-dose (HD) imatinib as second line treatment for chronic phase CML. Blood samples from at total of 102 CML patients with early or late chronic phase disease were collected prior to and six weeks after treatment with either 400 mg/day for 12 months or 800 mg/day for 6 months followed by 6 months of 400 mg imatinib therapy. Whole blood samples preserved by PAX gene technology were further processed and evaluated centrally at the expression profiling core facility at Innsbruck Medical University. For expression profiling samples were subjected to hemoglobin mRNA reduction before target preparation for hybridization to Affymetrix hGU133 Plus 2 genechips detecting ∼47000 transcripts thereby allowing a whole genome profiling approach. For response prediction we used both the linear discriminatory analysis (LDA) and a random Forest (RF) decision tree algorithm provided in Bioconductor software packages for the open source statistical language “R”. A 100- or 10-fold crossvalidation was performed using a robust leave-10-out setting for LDA and RF respectively. The planned interim analysis of clinical data from 76 evaluable patients undergoing 12 months of therapy with daily doses of 400 mg or 800 mg imatinib revealed 50 (66%) patients with and 26 (34%) patients without a major cytogenetic response (<35% Ph+ metaphases). We found, irrespective of imatinib dosing, a predictive gene expression signature for achieving a major cytogenetic response after 12 months of imatinib therapy. This predictive gene set comprises five genes (ENTPD4, F5, SCL22A4, AIM2, TLR5, PXK) achieving a correct prediction rate of 87% within the 6-week-treatment patient subgroup and an overall prediction rate of 76%. In conclusion, this is the first prospective gene expression profiling study in CML indicating a gene expression profile predicting major cytogenetic response, which still represents a robust response parameter for long-term outcome during imatinib therapy of patients with early or late chronic phase CML.