bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thalidomide and Dexamethasone Induction Therapy Is Associated with Superior Progression-Free Survival after Autotransplant for Myeloma.
Authors: Vogl Dan T. , Luger Selina , Porter David L. , Chong Elise A. , Schuster Stephen J. , Tsai Donald E. , Perl Alexander , Loren Alison W. , Goldstein Stephen , Nasta Sunita D. , Andreadis Charalambos , Mangan Patricia A. , Hummel Kimberly , Siegel Donald L. , Glatstein Eli , Stadtmauer Edward A. 
Published: April 2020

Abstract
BACKGROUND: High-dose melphalan with autologous stem cell support improves survival when incorporated in the initial treatment of multiple myeloma. Published data show that induction thalidomide and dexamethasone (Thal/Dex) has a higher response rate than dexamethasone alone (Dex) or anthracycline induction (VAD or DVD), but the effect of initial induction therapy on outcomes after autologous transplant remains unclear.
PATIENTS: We reviewed the records of 164 patients who received high-dose melphalan with autologous stem cell support as part of initial therapy for multiple myeloma at the University of Pennsylvania. Median age was 55 years (range 25 – 72). Durie-Salmon stage at diagnosis was II in 27% and III in 70% of patients. Induction regimens included VAD (62%), DVD (12%), Thal/Dex (11%), Dex (5%), and more than one regimen (10%). Post-transplant therapies for consolidation or maintenance included thalidomide (7%), interferon (23%), tandem autologous transplant (4%), non-myeloablative allogeneic transplant (7%), autologous co-stimulated T-cell infusion (14%), or observation until progression (45%). Patients who received Thal/Dex initial therapy were not significantly different than those receiving anthracycline-containing induction regimens (VAD/DVD), except for lower serum creatinine (median 0.9 vs 1.1 mg/dl; p=0.01), with a trend toward lower beta-2 microglobulin (B2M) and correspondingly lower ISS stage.
RESULTS: Median overall follow-up is 29 months (range 7–120). Thal/Dex induction trended towards a higher Very Good Partial Response (VGPR) rate than anthracycline induction (29% vs 14%, p=NS) and a higher overall response rate (76% vs 68%, p=NS). All of the patients who received Thal/Dex as induction therapy are alive, with a median follow-up of 23 months (range 13 – 34), while overall survival in the anthracycline induction group is 85% at 2 years. Progression-free survival at 2 years is 93% for Thal/Dex induction and 58% for VAD/DVD (HR 0.12, p=0.039). The improvement in progression-free survival persists in Cox regression models that include creatinine and either B2M or ISS stage.
CONCLUSION: In myeloma patients who undergo autologous stem cell transplant, thalidomide and dexamethasone induction may result in improved progression-free survival compared with VAD or DVD. Further studies of initial therapies for myeloma should assess long-term outcomes after autologous transplant.
Progression Free Survival, By Initial Treatment Progression Free Survival, By Initial Treatment
A Screening and Intervention Program Reducing Mortality and Serious Morbidity Associated with Neonatal Alloimmune Thrombocytopenia.
Authors: Kjeldsen-Kragh Jens , Killie Mette K. , Tomter Geir , Golebiowska Elzbieta , Pedersen Helene , Randen Ingrid , Hauge Reidun , Aune Berit , Oian Pal , Dahl Lauritz B. , Pirhonen Jouko , Svenningsen Leif , Wergeland Hakon , Lindeman Rolf , Husby Henrik , Gronn Morten , Skogen Bjorn , Husebekk Anne 
Published: April 2020

Abstract
Background: Neonatal alloimmune thrombocytopenia (NAIT) is most frequently caused by antibodies against the human platelet antigen (HPA) 1a. The objective of the present study was to identify HPA 1a negative women, and to offer them an intervention program aimed to reduce morbidity and mortality of NAIT.
Methods: A total of 100,448 pregnant women were HPA 1 typed. The HPA 1a negative women were screened for anti-HPA 1a, which was quantified when present. Immunized women were referred to a university hospital for clinical follow-up, including ultrasonographic examination of the fetal brain. Caesarean section was performed 2–4 weeks prior to term with platelets from HPA 1bb donors reserved for immediate transfusion if petechiae were present and/or if platelet count was &lt; 35 × 109/L.
Results: Of all women typed 2.1% were HPA 1a negative. Anti-HPA 1a was detected in 210 of 1,990 HPA 1a negative women. A total of 170 pregnancies in 154 HPA 1a negative women were managed according to the intervention program. These women gave birth to 161 HPA 1a positive children of whom 55 had severe thrombocytopenia (&lt;50 × 109/L) including two with ICH. There were no intrauterine deaths. In 13 previously published prospective studies comprising 131,465 women of whom 2,290 were HPA 1a negative, there were 10 cases with severe NAIT-related complications (3 intrauterine deaths and 7 neonates with ICH), which are significantly higher than in our study (p &lt; 0.05).
Conclusions: The screening and intervention program seems to reduce mortality and serious morbidity associated with NAIT.
Immune-Mediated Thrombocytopenia in Patients Treated with Vancomycin.
Authors: von Drygalski Annette , Curtis Brian , Bougie Dan , Ahl Scott , Baker Kelty , Aster Richard H. 
Published: April 2020

Abstract
Numerous drugs are known to cause immune thrombocytopenia (TP) mediated by antibodies (abs) that bind to platelets only when the sensitizing drug is present in soluble form. The widely used antibiotic, vancomycin, has been implicated as a cause of TP only in 8 case reports and little is known about antibodies possibly responsible for this complication. We characterized clinical and serologic aspects of TP occurring in 39 patients during treatment with vancomycin. In this group, TP developed after 1–27 days of treatment (median 6 days) and plt nadirs ranged from 1,000 to 60,000 plts/uL (median 14,000 plts/uL). Bleeding occurred in 14 patients and contributed to a fatal outcome in 3. TP persisted for 1–17 days after discontinuing vancomycin (median 7 days). Platelets eventually returned to baseline in all surviving patients. Serum obtained after the onset of TP was studied for vancomycin-dependent, platelet-reactive abs by flow cytometry and by solid phase ELISA using immobilized plt glycoproteins (GP) as targets.
Vancomycin-dependent antibodies detected in patients and normal subjects IgG only IgM only IgG + IgM No antibody Total Patients with TP 21 (54%) 5 (13%) 13 (33%) (0)%) 39 Normal individuals 58 (21%) 4 (1%) 1 (0%) 210 (77%) 273
Results of flow cytometric studies are summarized above. All patients had IgG and/or IgM abs that reacted with normal plts in the presence, but not in the absence of vancomycin. The IgG mean fluorescence intensity (MFI) signal in the presence of drug was 1.6 to 32.0 times stronger (mean ratio 5.7) than that obtained in the absence of drug. Vancomycin-dependent IgG abs were also identified in 59 of 273 normal individuals but were much weaker than abs detected in patients (p = 0.004). IgM abs (mean ratio 5.7, range 1.6 – 34) were found in 18 of 39 patients (46%). Weaker IgM abs were found in only 5 of 273 normal subjects (1.8%) (p = 0.001). Two patient abs studied in ELISA reacted preferentially with GPIIb/IIIa. Studies to determine the frequency of abs in patients given vancomycin who do not develop TP are in progress.
These findings provide evidence that TP in patients given vancomycin can be caused by drug-dependent abs specific for GPIIb/IIIa that are stimulated by vancomycin exposure. IgG and IgM abs in patients with TP are generally much stronger than drug-dependent, platelet-reactive immunoglobulins found in some normal subjects. The significance of the latter abs is presently unknown. Drug-dependent IgM abs are found almost exclusively in patients with vancomycin-associated TP and may be diagnostic. Patients treated with vancomycin often have life-threatening bacterial sepsis and may have various reasons for developing TP. Serologic testing for drug-dependent, platelet-reactive IgG and IgM abs may provide a means of identifying those in whom vancomycin should be discontinued.
A Hypomorphic Cbfb Allele Reveals a Critical Dosage-Sensitive Function of Core Binding Factors at the Earliest Stages of T Cell Development.
Authors: Maillard Ivan , Talebian Laleh , Li Zhe , Guo Yalin , Sugiyama Daisuke , Speck Maren E. , Pear Warren S. , Speck Nancy A. 
Published: April 2020

Abstract
The family of core binding factors includes the DNA-binding subunits Runx1-3 and the common non-DNA binding partner CBFβ. Runx1 and CBFβ are essential for the emergence of hematopoietic stem cells during fetal development, but not for stem cell maintenance during later ontogeny. Runx1 is also required for megakaryocyte differentiation, B cell development, and for the DN2 to DN3 transition in thymocyte development. Runx2/CBFβ are critical for normal osteogenesis, and Runx3 for CD4 silencing in CD8+ T cells, but their contribution to other steps of hematopoietic development is unknown. To examine the collective role of core binding factors in hematopoiesis, we generated a hypomorphic Cbfb allele (Cbfbrss). CBFβ protein levels were reduced by approximately 2–3 fold in fetuses homozygous for the Cbfbrss allele (Cbfbrss/rss), and 3–4 fold in fetuses carrying one hypomorphic and one knockout allele (Cbfbrss/−). Cbfbrss/rss and Cbfbrss/− fetuses had normal erythroid and B cell development, and relatively mild abnormalities in megakaryocyte and granulocyte differentiation. In contrast, T cell development was very sensitive to an incremental reduction of CBFβ levels: mature thymocytes were decreased in Cbfbrss/rss fetuses, and virtually absent in Cbfbrss/−fetuses. We next assessed the development of Cbfbrss/rss and Cbfbrss/− fetal liver progenitors after transplantation to irradiated adult recipients, in competition with wild-type (wt) bone marrow cells. Wt, Cbfbrss/rss and Cbfbrss/− fetal progenitors replenished the erythroid, myeloid and B cell compartments equally well. The overall development of Cbfbrss/rss T cells was preserved, although CD4 expression was derepressed in double negative thymocytes. In Cbfbrss/− chimeras, mature thymocytes were entirely derived from competitor cells. Furthermore, the developmental block in Cbfbrss/− progenitors was present at the earliest stages of T cell development within the DN1 (ETP) and DN2 subsets. Our data define a critical CBFβ threshold for normal T cell development, and they situate an essential role of core binding factors during the earliest stages of T cell development. In addition, early thymopoiesis appeared more severely affected by reduced CBFβ dosage than by the lack of Runx1 (Ichikawa et al., Nat Med 2004; Growney et al., Blood 2005), suggesting that Runx2/3 may contribute to core binding factor activity in the T cell lineage.
Newly Developed ADAMTS13 Antigen Assay Reveals Marked Ethnic Differences and Depletion in Acquired Thrombotic Thrombocytopenic Purpura.
Authors: Feys Hendrik B. , Liu Fang , Dong Ningzheng , Pareyn Inge , Vauterin Stephan , Vandeputte Nele , Ruan Changgeng , Hans Deckmyn , Karen Vanhoorelbeke 
Published: April 2020

Abstract
ADAMTS13 is a metalloprotease that cleaves the A2-domain of von Willebrand factor, resulting in a normal processed protein. A defective or blocked enzyme causes a severe disorder, called thrombotic thrombocytopenic purpura (TTP). The need for research tools, both clinical and fundamental, hence is urgent. To bypass the need for substantial amounts of highly purified antigen in order to produce monoclonal antibodies, we used genetic immunisation and an ADAMTS13 specific screening assay. Using this assay, high affinity hybridoma clones were selected and allowed us to set up a sensitive and reproducible sandwich ELISA. This antigen test is specific, as (i) plasma from a patient with acquired TTP but presenting without inhibitor, did not contain antigen and (ii) the binding of recombinant ADAMTS13 was inhibited by increasing amounts of ADAMTS13 in normal plasma. Antigen levels were measured relative to a standard of pooled normal human Caucasian plasma (n=20) that was arbitrarily set to 1 U/mL. Antigen levels in congenital TTP samples (34 ± 21 mU/mL, n =2) (mean ± SD) as well as in samples from patients with acquired TTP (231 ± 287 mU/mL, n=11) were clearly reduced when compared to normal Caucasian donors (951 ± 206 mU/mL, n=16). The samples from the above mentioned acquired TTP patients were taken before plasma exchange (PE). We found that antigen levels (513 ± 223, n = 11) raised significantly after PE therapy.
Figure Figure
Hence, ADAMTS13 antigen is severely reduced (&lt; 0.23 U/mL) at presentation in most (81%) of the investigated acquired TTP cases. Therefore, ADAMTS13 antigen is an important parameter in both congenital and acquired TTP. We also showed that the antigen assay could distinguish mutation carriers (341 ± 125 mU/mL, n = 9) from non-carriers (668 ± 208 mU/mL, n = 11) within a genotyped family of a congenital Chinese TTP patient. We also found that normal Chinese donors have a significantly lower antigen titre (601 ± 129 mU/mL, n=15) than Caucasian normals. The consequences of this finding, on the molecular level, are however not clear.
Figure Figure
Sensitivity and Efficacy in Measurement of Anti-Platelet Medications.
Authors: Blain Rachelle , Nakagawa Peggy , Belvedere Melissa , Scherer Monika , Nugent Diane 
Published: April 2020

Abstract
INTRODUCTION: Large prospective studies must be performed to measure the true effect of clopidogrel (Plavix) or aspirin (ASA) in prevention of vascular disease. An easy and accurate point of service instrument will facilitate these studies and confirm effectiveness and compliance with medications. With such a variety of equipment available for analysis of platelet dysfunction, it is important to understand the sensitivity and efficacy of each assay when evaluating patients. We have found significant differences in our comparative studies of the PFA-100, optical aggregation, and Thrombelastograph (TEG) platelet coagulation in normal individuals using Plavix or ASA.
METHODS: We have compared these three techniques to evaluate their effectiveness in assessing ASA and Plavix inhibition of platelet function. Eighteen normal individuals, who had been examined previously for ASA effect on these instruments, were studied at baseline and after three days of Plavix 75mg daily. All samples were drawn and run simultaneously. The TEG platelet coagulation assay used whole blood in a sodium heparin tube instead of a 3.2 % citrate tube which was used for aggregation and the PFA-100. The PFA-100 whole blood assays included both collagen-epinephrine (EPI) and collagen-adenosine diphosphate (ADP) cartridges. The TEG platelet coagulation assays were run with arachidonic acid (AA) and adenosine diphosphate (ADP) as agonists. The optical aggregation used platelet rich plasma with AA and ADP agonists.
RESULTS: We found significant differences between the PFA-100, TEG platelet function, and standard optical aggregation in measurement of Plavix effect. Optical aggregation and the TEG platelet assay did show the effects of Plavix, with the aggregometer being more sensitive than the TEG platelet assay although much more time consuming. In additional studies, the Plavix inhibition became more striking in the TEG by extending treatment to 6 days, suggesting that future studies should be done after a week (rather than 3 days) to see full effect. In contrast, Plavix effect was absent on the PFA-100. All three assays did show the effects of ASA in previously identified aspirin- responsive individuals. Ideally, one instrument could be used to assess response to both agents. However, the sensitivity of the instrument and the pharmacology of these and future medications must play an important role in the selection of which assay will be most informative for these large population studies in the prevention of vascular disease.
Figure Figure
Incident TTP: Plasmapheresis Therapy-Related Complications Are Common.
Authors: Zakarija Anaadriana , McCaffrey Kathryn R. , Bandarenko Nicholas , Pandey Dilip , Cursio John , Tevar Amul , Kwaan Hau , Yarnold Paul R. , Burton Maddie , Bennett Charles L. 
Published: April 2020

Abstract
Background: Plasmapheresis is the mainstay of therapy for thrombotic thrombocytopenic purpura (TTP). Due to the significant mortality associated with TTP if left untreated and the effectiveness of therapy, plasmapheresis may be instituted before the diagnosis is clearly established. Our case-control study of incident TTP allowed us to evaluate the incidence of complications in cases treated at multiple sites across the United States.
Methods: The SERF-TTP study is a NHLBI-funded 15-site study to identify 300 cases of incident TTP and 600 age and gender-matched community controls. Each case of incident TTP is identified upon referral for therapeutic plasma exchange (TPE). Exclusion criteria include solid organ or allogeneic stem cell transplant, anti-neoplastic therapy, or metastatic adenocarcinoma. Epidemiologic information, laboratory data, and plasma samples are collected from both patients and controls. In addition, information is collected about volume of TPE, frequency, type of replacement fluid, duration of TPE, adverse reactions associated with TPE, and concurrent therapy.
Results: To date, 11 sites across the US have IRB approval, and 50 cases have been identified. Data are available for the first 32 patients, whose mean age is 41.9 years. All patients underwent TPE, a number of which received more than one type of replacement fluid. The majority of patients received fresh frozen plasma (FFP): 60.0% FFP, 46.7% cyroprecipitate poor plasma, and 16.7% albumin. Additionally, 63.3% of patients received concurrent corticosteroid therapy. The mean number of treatment days prior to the achievement of platelet count &gt; 150,000 per microliter was 9.7 (range 0–43 days). Overall survival was 90.0%. Adverse reactions were observed in 53.3% of patients (16/30). The most frequently observed toxicity was an allergic reaction in 40% (12/30) of patients, followed by citrate-related toxicity in 30% (9/30) of patients. No patients experienced an anaphylactic reaction. 16.7% of cases (5/30) had venous access complications, most frequently a catheter-associated thrombosis (3/5). In addition, one patient had a significant hemorrhage associated with venous access, which required treatment in intensive care.
Conclusions: Preliminary data from this cohort of patients suggest that adverse reactions are commonly seen in incident TTP patients undergoing TPE; the most frequent are allergic reactions to plasma. This highlights the need for development of reliable diagnostic criteria for TTP so patients are not exposed to the risks of TPE unnecessarily.
Assessment of Bleeding in Thrombocytopenic Patients (pts) with Immune Thrombocytopenic Purpura (ITP).
Authors: Page Lemke K. , Elish Andrew S. , Provan Drew , Myrint Steven , Hamilton Michael , Jenkins Julian , Bussel James B. 
Published: April 2020

Abstract
Introduction: Assessment of bleeding in ITP is difficult. There is no agreed upon methodology; the WHO bleeding score does not seem useful for ITP. We report an ITP bleeding score including the relationship between site-specific bleeding severity (BLS), platelet count (plt ct), and plt size.
Methods: A bleeding score was created which has 11 sites, 9 by history (Hx) of the previous week: skin, oral, epistaxis, GI, GU, GYN, hemoptysis, subconjunctival (SC), and intracranial hemorrhage (ICH); and 2 by Exam (PE): skin and oral. The BLS grades (gr) pts for each site on a defined scale from no bleeding (0) to “major” bleeding (2). Plt cts and large plts (LP) were measured on the Bayer Advia 120. No pt had &gt; 2 study visits.
Results: The 65 ITP pts on 100 visits over 6 months had a median (mdn) plt ct of 41,500/uL (41.5k). The mdn age was 31.5 yrs; 20 pts were children. 56 pts had chronic ITP, 26 s/p splenectomy, with a mdn duration of ITP of 6 yrs. There were no GU, SC hemorrhage (hem), or ICH. 72% of all gr 1 hem’s were skin whereas 46% of gr 2 hem’s were oral. There was 1 GI hem and 3 hemoptysis visits that were gr 2. 42 women on 63 visits had 5 visits each with GYN BLS gr 1 and gr 2. X2 testing correlated plt ct and BLS for 6 sites: both oral and both skin sites, epistaxis, and GYN (p’s &lt; 0.05). Oral PE correlated best with the plt ct (fig 1). For oral PE, BLS of gr 2 did not occur at plt cts &gt; 20k.
When the BLS was scored independently by two observers (LKP & JB) on 63 of the100 visits, 92% of individual BLS grs were identical (PearsonR=0.75). Skin PE and epistaxis each had 11/63 discrepancies. In addition, 16 BLS for oral (15 for skin) were different comparing Hx and PE (fig 2).
LP did not correlate well with site-specific BLS when only plt cts ≤ 30k were included, suggesting that large, young platelets may not primarily determine bleeding severity in ITP. However for Skin Hx, if the BLS was gr 0, 4/6 had LP ≥ 2 whereas only 7/28 LP were ≥ 2 when the BLS was gr 1.
Conclusions: The Bleeding Score reported here was validated by: a) the relationship of bleeding severity at multiple sites to plt ct including the absence of gr 2 bleeding at plt cts &gt;20k; and b) the high degree of interobserver reliability despite a low but irreducible error rate based on variability in pt recall. It takes ≤ 3–5 minutes to complete. The significance of LP remains unclear. Studies of the BLS in larger numbers of patients will further determine its usefulness.
Figure 1. Bleeding Severity for Oral Cavity (PE) Versus Platelet Count Figure 1. Bleeding Severity for Oral Cavity (PE) Versus Platelet Count
Figure 2. Comparision of Oral PE to Oral Hx Figure 2. Comparision of Oral PE to Oral Hx