bluuebunny/crossref_metadata_2025_split huggingface dataset:
An Enriched Multigen Low-Density Array To Predict Outcome in Advanced Hodgkin Lymphoma Paraffin-Embedded Samples.
Authors: Sanchez-Espiridion Beatriz , Sanchez-Aguilera Abel , Montalban Carlos , Garcia-Cosio Monica , Bellas Carmen , Romagosa Vicente , Menarguez Javier , Fresno Manuel F. , Tomas Jose F. , Morente Manuel M. , Piris Miguel A. , Garcia Juan F. 
Published: April 2020

Abstract
Despite the major advances in the treatment of classical Hodgkin Lymphoma (cHL) patients, around 30% to 40% of cases in advanced stages may relapse or die as result of the disease, and current markers to predict prognosis are rather unreliable. The identification of molecular events and biological processes associated with treatment failure are essential to develop new predictive tools. We used gene expression data from 29 samples of advanced cHL patients and HL-derived cell lines in order to identify transcriptional patterns from both tumoral cells and cell microenvironment. Student t-test was used to detect genes differentially overexpressed in cell lines and in tumor samples, thus creating two databases that report for genes expressed by the tumor HRS cells and genes expressed by the microenvironment. Using Gene Set Enrichment analysis (GSEA) we identified specific gene sets enriched in both databases in patients with favorable and unfavorable outcome, respectively. To validate these pathways we designed a novel Taqman low-density array (LDA) to examine the expression of the most relevant genes in 60 formalin-fixed, paraffin embedded (FFPE) tissue samples, and correlated the results with treatment outcome. Functional pathways related to unfavorable outcome significantly enriched in the HRS cells included the regulation of the G2/M checkpoint of the cell cycle, S phase and G1/S transition, chaperons, histone modification and other signaling pathways with an important representation of the MAPK pathway. On the other hand, genes reporting for specific T-cell populations (T-cytotoxic and T-regulatory cells) and macrophage activation were found to be overexpressed in the microenvironment. The final model presents a balanced representation of these genes, including also genes encoding factors implicated in drug resistance (RRM2, TYMS and TOP2A). RNA extracted from FFPE sections yielded analyzable data for 80% of samples. LDA analysis of the genes included in the model confirmed the feasibility of this approach, and the capacity for identifying cases with increased risk of failure.LDA provides an effective technique for analyzing gene expression in FFPE tissues, and it can be used for clinical prediction in diagnostic samples, using a selection of genes identified after GSEA analysis of the initial molecular signatures. This novel Taqman LDA will be used to develop a new molecular predictor of the outcome of patients with advanced cHL.
Bortezomib Alone or in Combinination with Doxil Is Active in Adult Refractory Multi-System Langerhans Cell Histiocytosis (LCH).
Authors: Haddad Philip A. 
Published: April 2020

Abstract
Langerhans cell histiocytosis (LCH) is a clonal disorder of activated Langerhans cells. LCH is characterized by increased proliferation index, Ki-67, as a result of dysregulation of anti-apoptotic pathways (Bcl-2) and cell cycle regulators (p53-p21 and p16-Rb pathways). Although current available therapies are very effective at inducing remission, treatment of LCH remains problematic due to multiple recurrences and eventual fatalities in a significant proportion of young patients. More effective therapies based on the pathogenesis of LCH are needed. We investigated the use of Bortezomib, a proteosome inhibitor with a reported antiproliferative effect on plasma cells and lymphocytes, in a heavily pre-treated patient with recurrent multi-system LCH involving lungs, bones, skin and pituitary gland and who was previously treated with and progressed on Vinblastine, Steroids, Peg-Interferon, Methotrexate/ 6MP. The patient received Bortezomib initially at 1.3 mg/m2 days 1, 4, 8, 11 Q 21 days (cycles 1&2) which was reduced to 1.0 mg/m2 days 1, 4, 8, 11 Q21 days (cycles 3&4) and then to 1.0 mg/m2 weekly for cycle#5 due to grade 3 exacerbation of his baseline Vinblastine induced peripheral neuropathy. Patient’s skin disease achieved very early response after cycle 1 with PR as maximum response after cycle 2. Such response was maintained until the patient was switched to weekly dose. Stable disease was observed at other sites especially the pituitary mass. Upon flaring of his skin disease, patient was started back on Bortezomib 1.0 mg/m2 days 1, 4, 8, 11 along with Doxil 30mg/m2 on day 4 Q21 days, to explore their reported synergy. After cycle 1, patient achieved a very good PR as far as his skin disease and CR after the 3rd cycle. His pituitary LCH mass was also noted to decrease by 20% with visual improvement. Unfortunately, due to grade 3 fatigue and anorexia, therapy was stopped. However, responses are still maintained for 3 months so far. Hematologic toxicities were limited to Grade 1 neutropenia, anemia, and thrombocytopenia. Bortezomib has activity on its own and synergies with Doxil in recurrent and heavily pre-treated multisystem LCH. Its incorporation into front-line treatment of patients with multi-system LCH needs further study.
Incidence and Risk Factors for Agranulocytosis in Latin American Countries - The LATIN Study.
Authors: Hamerschlak Nelson , Maluf Eliane , Eluf Jose , Cavalcante Alexandre B. , Pasquini Ricardo , Lorand-Metze Irene , Falcao Roberto P. 
Published: April 2020

Abstract
The association of agranulocytosis with the use of many different drugs has been documented. LATIN is a case-control study designed to identify risk factors for agranulocytosis and aplastic anemia, including drugs, and to estimate the incidence rates of both diseases in some Latin American countries. This report will cover just agranulocytosis. In 4 years, 52 cases of agranulocytosis were diagnosed. The overall incidence rate was 0.38 cases per 1 million inhabitant-years (0.35 for Brazil, 2.09 for Argentina, and no case verified in Monterrey, Mexico). Agranulocytosis patients more often took medications already associated with agranulocytosis than controls (76.7% of cases and 52.5% of controls; OR 3.7, 95% CI 1.3–12.5; p = 0.01), the most important being methimazole (OR 44.2, 95% CI 6.8 to infinite). The population attributable risk percent (etiologic fraction) was 56%. The use of nutrients supplements was more frequent among agranulocytosis patients than controls (p = 0.03). The agranulocytosis incidence in Latin America was lower than that of European countries and Israel. The rarity of the disease indicates that it is not a public health problem, and there is no reason for major protection measures other than improving diagnostic tools and making earlier agranulocytosis diagnosis.
The Prognostic Role of Clinical and Microbiological Factors on Mortality Related to Candida Bloodstream Infections in Hospitalized Patients with Hematologic Malignancies.
Authors: Bigni Ricardo S. , Velasco Eduardo D. , Dobbin Jane A. 
Published: April 2020

Abstract
Between January 2001 and June 2005 a prospective cohort study of hospitalized patients with hematological malignancies including 47 adults and 30 children with candidemia was conducted at a tertiary oncology care center in Brazil in order to compare the epidemiological characteristics, concurrent illnesses and the clinical microbiological data of both groups that may influence the outcome. The crude mortality was higher in the adult population than in children (46,8% vs. 20,0%) (figure 1). A univariate analysis indicated that in the adult population were lymphoma, neutropenia, presence of comorbidities, a non-removed central venous catheter (CVC), a poor performance status, lack of CVC, use of steroid, hepatic dysfunction, previous surgery, hypotension and severe respiratory dysfunction were risk factors significantly associated with death. Among children the predictors of mortality were acute leukemia, neutropenia, presence of comorbidities, lack of CVC, poor performance status, hypotension, concomitant infected sites, pulmonary infiltrates and severe respiratory dysfunction. Although no major differences was detected in survival rates following fungemia with C. albicans and all Candida non-albicans species, episodes with Candida glabrata, krusei and tropicalis subgroup species had the highest crude death rate compared with C. albicans and other isolates (59,4% vs. 35,3% vs. 10,7%; P&lt;0.01) (figure 2). Candidemia due to C. parapsilosis was associated with the lowest mortality rate. Two variables remained statistically associated with mortality among adults in the multivariate analysis: CVC retention (OR 6.41; 95% CI 1.04–39.55) and presence of comorbidities (OR 2.17; 95% CI 1.33–3.53). Among children only the presence of comorbidities (OR 2.61; 95% CI 1.46–4.66) affected independently the outcome. Our data demonstrate children had a significant lower mortality rate than adults, despite the higher incidence of candidemia in this lower age subjects. There were significant differences of epidemiological, clinical characteristics and other risk factors between both groups. Concurrent comorbidities were the most important independent prognostic factor in both groups of patients.
An Individual Platelet Count Set-Point in ITP: A Concept Learned from Patients with Mild Thrombocytopenia and a Good Response to IVIg or Corticosteroids.
Authors: Arnold Donald M. , Moore Jane C. , Smith James W. , Kelton John G. 
Published: April 2020

Abstract
Background: Immune thrombocytopenic purpura (ITP) is a heterogeneous disease caused by both increased platelet destruction and decreased platelet production. Thrombocytopenia is typically severe, and in the absence of a sensitive and specific test, a platelet count response to intravenous immune globulin (IVIg) or corticosteroids is diagnostic. Patients with mild thrombocytopenia (platelets 50 – 150 × 109/L) may have ITP, non-immune thrombocytopenia or a low-normal platelet count. The diagnostic value of platelet autoantibodies for such patients is not known.
Methods: We studied the platelet count responses of 6 patients with mild thrombocytopenia who were treated with either IVIg or corticosteroids. Baseline platelet count was defined as the mean of the 2 lowest, consecutive platelet counts that were within 15% of each other. The peak platelet count was the highest recorded platelet count measured within 1 month of treatment. For most patients, the dose of IVIg was 1g/kg ×1, and the dose of prednisone was 1mg/kg for 2 – 4 weeks. Complete response was defined as a peak platelet count that was at least 2x baseline; a partial response was defined as a peak platelet count 1.5 – 2x baseline; below that was not considered a response. Platelet glycoprotein IIb/IIIa and Ib/IX autoantibodies were determined by the antigen capture assay using platelet lysates prepared from samples collected prior to treatment. An OD &gt;0.4 was considered positive.
Results: Five patients with mild thrombocytopenia received 5 treatments with IVIg and 2 treatments with corticosteroid (2 patients received IVIg on 2 separate occasions). The indications for treatment were: planned invasive procedure (n=5), pregnancy/delivery (n=1), and treatment of multiple sclerosis (n=1). Patients were followed for a median of 1.6 years (range 0.6 – 3 years). Median baseline platelet count prior to treatment was 70 ×109/L (range 57 – 79 ×109/L). A platelet count response was observed following all 7 treatments; including 5 complete responses and 2 partial responses. Median peak platelet count was 180 ×109/L (range 115 – 297 ×109/L). Post-treatment platelet counts returned to within 15% of pre-treatment values following 6 of 7 treatments after a median of 3 months (range 1 week – 5 months). Of the 3 patient tested, none had anti-GP IIb/IIIa or anti-Ib/IX autoantibodies.
Interpretation: A good response to IVIg (or steroid) treatment confirmed the immune nature of mild thrombocytopenia in this cohort and should be used as the gold standard to evaluate the test characteristics of platelet autoantibodies. We observed that some patients with mild ITP have an individual platelet count “set-point” which remained relatively stable over time. Although further testing is required, this concept implies that in some patients, there is a regulated balance between platelet destruction and underproduction.
Distribution of Hypercoagulation Laboratory Diagnoses among Patients with History of Thromboembolic Disease.
Authors: Bern Murray M. , McCarthy Nancy , Bonner Jamie 
Published: April 2020

Abstract
This abstract demonstrates the distribution of hypercoagulation diagnosis among patients with histories of thromboembolic disease (TED) among a group of patients detected at surgery prescreening clinic or through other referral sources. The consulting hematologists determined which laboratory tests were ordered; thus not all patients had all tests. This abstract describes the results of those clinical consultations. For this study the hospital’s computer logs were probed for patients having had measurements of protein C and factor V Leiden from 11/7/01until 8/1/07. The laboratory records of identified patients were searched for additional hypercoagulation laboratory parameters. A total of 383 patients have been identified, among whom abnormal diagnostic results were found for 231. Genomic assays were performed often for the commonly found defects (i.e., factor V Leiden and prothrombin 20210) and selectively for other situations, such 4G/5G for patients with elevated plasminogen activator inhibitor 1 (PAI-1) and unresolved venous thrombus, or methylene tetrahydrofolate (MTH) reductace for unexplained elevation of homocysteine. The table demonstrate the distribution of these laboratory diagnoses. The risk of having TED associated with these results will be stratified to emphasize the increased risk associated with the more severe abnormalities of protein C, protein S, ATIII, PAI-1, and homocysteine. These results demonstrate that laboratory explanations for TED may be found in a large proportion of patients with TED, which thereafter can be used to design prophylactic programs for at risk patients upon entry to hospital, especially elective surgery.
Hypercoagulation Parameters Patients Protein C* (&lt;60%) Protein S* (&lt;60%) AT III (&lt;80%) Homocysteine (&gt;12 um/L) Lupus anticoagulant Anti-phospholipid syndrome** * excludes patients taking warfarin; includes functional and antigen assays. ** combines anticardiolipin; anti-beta2, glycoprotein1; and anti-phosphotidyl -serine, -ethanolamine and -choline antibodies. total n 350 358 244 252 166 234 abnormal n (%) 7(2) 64(18) 29 (12) 89(35) 18 (11) 41 (18) PAI-1 (&gt;42) ng/ml) APC Resistance (&lt;2.1) VIII:c & VIII:vW (&gt;180%) Factor V Leiden Prothrombin 20210 MTH Folate Reductace 4G/5G 36 75 61 225 219 10 9 22 (61) 10 (13) 11 (18) 37 (16) 16 (7) 8 (80) 8 (90)
Characterization of Heparin Binding Site Residues on the Catalytic Domain of Factor XIa
Authors: Yang Likui , Sun Mao-fu , Manithody Chandrashekhara , Gailani David , Rezaie Alireza R. 
Published: April 2020

Abstract
The basic residues of the 170-helix (chymotrypsinogen numbering) in the catalytic domain of the procoagulant serine proteases are known to interact with heparin and facilitate their rapid inhibition by specific plasma serpins. The homologous loop of factor XIa possesses three basic residues (Lys-170, Arg-171 and Arg-173). To investigate the role of these residues in the heparin-mediated inhibition of fXIa by C1-inhibitor (C1-INH) and antithrombin (AT), we expressed the monomeric light chain fragment of fXIa containing only the catalytic domain of the protease in wild-type and mutant forms in which the three basic residues of the 170-helix have been substituted individually, or in combinations, with Ala. The catalytic properties of fXIa derivatives were compared to wild-type fXIa (fXIa-WT) with respect to their ability to hydrolyze the chromogenic substrate S2366 and to undergo inhibition by C1-INH and AT in the absence and presence of heparin. All mutants exhibited normal amidolytic activity, hydrolyzing S2366 with catalytic efficiencies similar to fXIa-WT. All mutants were also inhibited by both C1-INH and AT with normal rate constants in the absence of heparin. However, the heparincatalyzed inhibition of mutants by both serpins differed to varying degrees relative to fXIa-WT, with the Arg-171 to Ala substitution mutant exhibiting ~3-fold lower rate of inhibition by C1-INH and requiring ~3-fold higher concentration of heparin for observing optimal inhibitory effect. In reactions with AT, all three basic residues appeared to make similar contributions to the heparin-catalyzed inhibition of fXIa by the serpin as evidenced by all three mutants exhibiting dramatically lower inhibition rate constants in the presence of heparin. A bell-shaped heparin concentration dependence for the fXIa inhibition by both serpins suggested that the template effect of heparin primarily accounts for the acceleration mechanism. However, a comparison of the heparin bell-shaped dependence inhibition of the dimeric plasma-derived wild-type fXIa with that of the isolated single chain catalytic domain suggested that the optimal concentration of heparin for the acceleration of the protease has been increased from ~50 nM for the dimeric protease to ~250 nM for the isolated catalytic domain, possibly suggesting further contribution to affinity of the fXIaheparin interaction from the Apple-3 domain of the non-catalytic domain on which a binding-site for heparin has been reported.
Predicting Response to Immunosuppressive Therapy in Childhood Aplastic Anemia.
Authors: Yoshida Nao , Yagasaki Hiroshi , Kosaka Yoshiyuki , Kobayashi Ryoji , Yabe Hiromasa , Kaneko Takashi , Tsuchida Masahiro , Ohara Akira , Nakahata Tatsutoshi , Kojima Seiji 
Published: April 2020

Abstract
Aplastic anemia (AA) is defined as a pancytopenia caused by bone marrow failure; its pathogenesis is thought to involve autoimmune processes. Immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine (CyA) provides response rates of 50–70% for children with AA, but predictive markers of response to therapy have not been well defined. We previously investigated the clinical relevance of HLA, a minor population of paroxysmal nocturnal hemoglobinuria-type cells, and a specific auto-antibody associated with AA in pediatric patients and reported that there was no correlation between these markers and response to therapy (Yoshida N, et al. Br J Haematol, 2008). In the current study, we prospectively evaluated whether clinical and laboratory findings before treatment, including age, sex, interval between diagnosis and treatment, etiology, severity of disease, white blood cell (WBC) count, neutrophil count, hemoglobin level, reticulocyte count, and platelet count, could predict the IST response at 6 months. Subjects included a large population of pediatric AA patients enrolled in a multicenter AA-97 study conducted by the Japan Childhood Aplastic Anemia Study Group. Between October 1997 and September 2006, 312 children (186 boys and 126 girls) younger than 18 years who were newly diagnosed with AA were enrolled in the study and treated with a combination of ATG and CyA. The median age at diagnosis was 8 years (range, 1–17 years). Of the 312 patients, 261 had idiopathic AA, 44 had hepatitis-associated AA, and 7 had AA from other causes. In terms of severity, 156 patients had very severe disease, 107 had severe disease, and 49 had moderate disease. The median interval between diagnosis and treatment was 15 days (range, 1–180 days). The overall response rate was 56%. In multivariate analyses, lower WBC count, shorter interval between diagnosis and therapy, and male sex were predictive markers of better response. Patients with WBC &lt;2500/μl had a significantly higher response rate than those with WBC ≥2500/μl (61 vs. 48%; P=0.008); this was the strongest predictor of response. Notably, response rate was inversely related to the interval between diagnosis and treatment; response rates of patients with an interval between diagnosis and treatment of &lt;30 and ≥30 days were 60% and 43%, respectively (P=0.02). Boys had a better response compared with girls (62 vs. 48%; P=0.02). In conclusion, pretreatment clinical and laboratory findings influence the response rate to IST. Response is well correlated with WBC count rather than neutrophil count or severity of disease. IST should be started as soon as possible after diagnosis of AA, given that the response rate worsens as the interval between diagnosis and treatment increases.
De Novo Deletion 17p13.1 Chronic Lymphocytic Leukemia Shows Significant Clinical Heterogeneity: The MD Anderson/Mayo Clinic Experience.
Authors: Tam Constantine S. , Shanafelt Tait D. , Wierda William G. , Abruzzo Lynne V , Van Dyke Daniel L. , Lerner Susan , Lynn Alice , Kay Neil E. , Keating Michael J 
Published: April 2020

Abstract
Figure Figure
In order to characterize the clinical course of patients (pts) with deletion 17p13.1 (17p-) CLL, we identified 100 consecutive treatment-naïve pts with 17p- from the MD Anderson Cancer Center (MDACC, n=61) and Mayo Clinic (n=39) clinical databases. The diagnosis of 17p- was established by FISH with a median time from initial diagnosis to FISH documenting 17p- of 9 months. Median age was 64 yrs (60 for MDACC pts & 70 for Mayo pts) and Rai stage was 0, 1–2 and 3–4 in 34%, 49% and 17% pts respectively. 17p- was the sole FISH abnormality in 29%. Unmutated IgVH and ZAP-70 positivity were present in 30/62 and 54/84 patients respectively. &lt;&lt;&lt;TIME TO FIRST THERAPY&gt;&gt;&gt; 69 asymptomatic pts were followed until they developed progressive disease requiring therapy as defined by the NCIWG 96 criteria. The 2 year actuarial risk of progression to initiation of therapy was 43% (46% for MDACC pts & 36% for Mayo pts). Only 2 of 10 pts with stable disease &gt;2 years progressed on prolonged follow-up of up to 54 months. Two pts with baseline 17p- in 10% and 13% of nuclei lost their 17p- clone after 23 and 41 months. Independent predictors of shorter time to treatment were Rai stage &gt; 0 (hazard ratio 7.2) and unmutated IgVH (HR 5.3). Pts with 0, 1 or 2 of these factors had a 2 year progression rate of 0%, 48% and &gt;75% respectively (p&lt;0.01). Other prognostic parameters such as ZAP-70 and CD38 did not have independent prognostic utility. &lt;&lt;&lt;RESPONSE TO THERAPY&gt;&gt;&gt; 41 pts from MDACC were assessable for response to first therapy. Overall (OR) and complete response (CR) rates were: rituximab without chemotherapy (n=6), OR 67% CR 17%; purine analogue + rituximab combinations (n=20), OR 75% CR 30%; purine analogue, rituximab + alemtuzumab combinations (n=13), OR 85% CR 54%. The pt who achieved CR after rituximab was negative for minimal residual disease assessed by flow cytometry and consensus primer IgH PCR, and has remained in remission at 29 months. At 2 years, 75% of complete responders remained relapse free. &lt;&lt;&lt;SURVIVAL FROM 17P- DIAGNOSIS&gt;&gt;&gt; Two year survival was 78%. Independent predictors of inferior survival were age 60+ (HR 3.4), B-symptoms (HR 3.7) and 17p- in nuclei 70+% (HR 6.0). Considering age 60+ and 17p- in nuclei 70+% in a prognostic model, 2 year survival was 100%, 82% and 55% for pts with 0, 1 and 2 risk factors respectively. Other prognostic parameters such as ZAP-70, IgVH mutation status and CD38 did not have independent prognostic utility. &lt;&lt;&lt;CONCLUSIONS&gt;&gt;&gt; Pts with de novo 17p- CLL exhibit marked clinical heterogeneity, with some pts experiencing an indolent course with prolonged survival. Survival and time to treatment among patients with 17p- can be predicted using clinical and biological characteristics.