bluuebunny/crossref_metadata_2025_split huggingface dataset:
Should High-Risk Patients with Chronic Atrial Fibrillation and Those with Coronary Artery Disease Receive Combined Aspirin-Oral Anticoagulant Therapy or Oral Anticoagulant Therapy Alone? A Systematic Review and Meta-Analysis.
Authors: Dentali Francesco , Lim Wendy , Douketis James D. 
Published: April 2020

Abstract
Background: Deciding between combined aspirin and oral anticoagulant (OAC) therapy compared to OAC therapy alone in patients with chronic atrial fibrillation who also have coronary artery disease or are at high risk for stroke is a common clinical problem. Individual trials do not address the benefits and risks of these two treatment strategies.
Purpose: To perform a systematic review and meta-analysis of randomized controlled trials comparing combined aspirin-OAC therapy and OAC alone with respect to bleeding complications and overall mortality.
Data Sources: Randomized trials published up to December 2004 in MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials databases.
Study Selection: Included studies satisfied the following criteria: randomized trial involving patients, age ≥18 years, with chronic atrial fibrillation, a mechanical heart valve or coronary artery disease that compared treatment with OAC and aspirin to treatment with OAC alone; OAC therapy was the same in all treatment arms; patient follow-up for at least 3 months; the study documented at least 2 of 3 study outcomes.
Data Extraction: Two reviewers independently extracted data on thromboembolic, major bleeding and mortality outcomes. Authors were contacted if the required information was not available.
Data Synthesis: Fifteen studies were included, totalling 8984 patients with a mechanical heart valve, chronic atrial fibrillation or coronary artery disease. The risk for thromboembolic outcomes was significantly lower in patients receiving aspirin-OAC therapy compared to OAC therapy alone (OR = 0.62; 95% CI: 0.51, 0.77; P &lt;0.001). In patients receiving aspirin-OAC therapy or OAC therapy alone, there was no difference in the risk for major bleeding (OR = 1.14; 95% CI: 0.90, 1.45; P = 0.27), intracranial bleeding (OR = 0.84; 95% CI: 0.51, 1.39), or fatal bleeding (OR = 1.36; 95% CI: 0.71, 2.61). There was no significant difference in all-cause mortality in patients receiving aspirin-OAC therapy compared to OAC therapy alone (OR = 0.93; 95% CI: 0.78, 1.10; P = 0.38). In patients receiving aspirin-OAC therapy compared to OAC therapy alone, there was no significant difference in the case-fatality rate for thromboembolism (12.1% vs. 12.2%; P = 0.99), or major bleeding (13.2% vs. 11.5%; P = 0.66).
Conclusions: Aspirin may be added to OAC in patients at high risk of thromboembolic complications since it appears to be effective with a similar bleeding risk as therapy with OAC alone. However, does not appear to reduce the risk of death.
Does Thromboprophylaxis Reduce Mortality in Medical Patients? A Systematic Review and Meta-Analysis of Randomized Cntrolled Tials.
Authors: Dentali Francesco , Gianni Monica , Lim Wendy , Douketis James D. 
Published: April 2020

Abstract
Background: Despite good evidence that anticoagulants are effective in preventing venous thromboembolism in medical patients at risk for this disease, only one-third of such patients are receiving thromboprophylaxis. Underutilization of thromboprophylaxis in medical patients may be due to lack of evidence that thromboprophylaxis reduces mortality, concerns about anticoagulant-related bleeding, and questions about the clinical significance of surrogate (venographic) outcomes to assess efficacy in these trials. We performed a meta-analysis of randomized, placebo-controlled trials of anticoagulant thromboprophylaxis in medical patients to assess effects on mortality and bleeding.
Methods: The MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials databases were searched until June 2005. Studies were included that were randomized, placebo-controlled trials investigated a prophylactic dose of unfractionated heparin, low-molecular-weight heparin, or fondaparinux in medical patients. Meta-analysis was done to obtain pooled estimates of the effects of anticoagulant thromboprophylaxis on mortality and clinically important (major) bleeding. The effect of treatment on venous thromboembolism was not pooled because of across-study difference in methods used to diagnose this, and use of asymptomatic (venographic) outcomes in some studies.
Results: There were 8 studies of 20,631 patients in the assessment of mortality and 4 studies of 5,428 patients in the assessment of major bleeding. Death occurred in 536 of 10,321 (5.2%) patients who received thromboprophylaxis, and in 608 of 10,510 (5.8%) who received placebo. Thromboprophylaxis was associated with 10% decreased risk for all-cause mortality, although this effect was not quite statistically significant (odds ratio [OR] = 0.90; 95% confidence interval [CI]: 0.81, 1.01). Major bleeding occurred in 22 of 2,726 (0.8%) patients who received thromboprophylaxis, and in 11 of 2,702 (0.4%) patients who received placebo. Thromboprophylaxis was associated with 2-fold increased risk for major bleeding, although this effect was not quite statistically significant (OR = 2.04; 95% CI: 0.98, 4.23).
Conclusion: In medical patients who are at increased risk for venous thromboembolism, anticoagulant thromboprophylaxis appears to confer a small reduction in mortality; this benefit should be balanced against an increased risk for major bleeding.
Anti-Xa Levels and Renal Function: Analysis of the First 32 Patients in the Tinzaparin in Renal Insufficiency for Venous Thromboembolism Study.
Authors: Lim Wendy , Douketis James , Wang Luqi , Woods Karen , Schnurr Terri , Kinnon Krystyna , Cruickshank Rebecca , Clase Catherine M. , Rabbat Christian , Crowther Mark A. 
Published: April 2020

Abstract
Background: Low-molecular-weight heparin (LMWH) is renally eliminated; its use in patients with renal insufficiency may be associated with accumulation and an increased bleeding risk. Due to its higher molecular weight and greater negative charge, tinzaparin may be less dependent on renal elimination compared to other LMWHs. As a result, tinzaparin may be less prone to accumulate in patients with renal insufficiency.
Purpose: To measure the anticoagulant effect of a 5-day course of therapeutic-dose tinzaparin used for the initial treatment of venous thromboembolism (VTE) in patients with varying degrees of renal insufficiency. We present the anti-Xa results of the first 32 patients enrolled in the study, correlated with renal function.
Design: Prospective cohort study.
Methods: In- and out-patients requiring therapeutic dose anticoagulation were enrolled and stratified into 4 groups based on creatinine clearance (CrCl): &gt; 60 ml/min, 30–60 ml/min, ≤ 30 ml/min and hemodialysis-dependent. Tinzaparin 175 IU/kg was administered once daily for 5 days or until the INR was ≥ 2.0 with warfarin therapy. Trough anti-Xa levels were measured prior to the 3rd (day 3) and 5th (day 5) tinzaparin doses. Patients with an anti-Xa level &gt; 0.5 IU/mL received tinzaparin dose adjustment using a standardized nomogram.
Results: The relationship between anti-Xa levels and CrCl is shown in figure 1. One patient with a CrCl of 47 ml/min had a day 3 anti-Xa level of 0.62 IU/ml and required dose adjustment, resulting in a day 5 anti-Xa of 0.22 IU/ml. There has been one minor bleeding event (hematoma) following a traumatic intravenous catheter insertion. No major bleeding or recurrent VTE events have occurred.
Conclusions: In a cohort of 32 patients with differing degrees of renal function including patients requiring hemodialysis, use of therapeutic-dose tinzaparin for 5 days does not appear to result in accumulation of the anticoagulant effects. There is no apparent correlation between anti-Xa level and renal function. Our results support ongoing evaluation of tinzaparin in patients with severe renal insufficiency.
Figure 1. Anti-Xa levels an renal function Figure 1. Anti-Xa levels an renal function
Estimated Annual Number of Incident and Recurrent, Non-Fatal and Fatal Venous Thromboembolism (VTE) Events in the US.
Authors: Heit John A. , Cohen Alexander T. , Anderson Frederick A. ,   on Behalf of the VTE Impact Assessment Group
Published: April 2020

Abstract
Background The total annual number of VTE events and related deaths in the US is unknown, largely because the complete spectrum of disease (including asymptomatic events and sudden deaths) occurring in the community is under-recognized.
Objective To estimate the total annual number of non-fatal and fatal deep vein thrombosis (DVT) and pulmonary embolism (PE) events (incident and recurrent) in the US.
Methods We developed an incidence-based model that included both hospital- and community-acquired VTE events as well as death from recognized and unrecognized VTE. We estimated the annual number of community-acquired events using the average age-, sex-, and event-specific incidence rates in Olmsted County, MN (1966–1990) and Y2000 US census data. We estimated the annual number of hospital-acquired events using patient age and Y2002 International Classification of Disease (ICD-9) discharge diagnosis codes for major surgery types or acute medical illnesses within the Healthcare Utilization and Cost Database, which includes major discharge diagnoses from all US acute-care hospitals. Patients were included in the hospital model if they were deemed at risk of VTE according to current American College of Chest Physicians definitions. The hospital at-risk population was divided into categories according to type of surgery or medical diagnosis on admission. We estimated the annual number of VTE events based on the published probability of VTE with and without prophylaxis, and US prophylaxis rates, by risk group. Fatal and recurrent events were estimated based on published data. The effects of VTE and prophylaxis rate uncertainty on our estimates were tested using sensitivity analyses.
Results The estimated total annual number of symptomatic VTE events in the US exceeded 600,000, (DVT, n=376,365; PE, n=237,058. Table).
Table. Annual Number of Non-Fatal and Fatal, Community- and Hospital-Acquired Symptomatic VTE Events in the US Event Type Community Hospital Total Non-Fatal ---------n---------- DVT 108,240 268,125 376,365 PE 85,358 151,700 237,058 Total 193,598 419,825 613,423 Fatal DVT 649 1,609 2,258 PE 105,902 188,210 294,112 Total 106,550 189,819 296,370
VTE-related deaths were estimated at 296,370 annually. Of these deaths, 21,223 (7%) patients were diagnosed with VTE and treated, 101,032 (34%) were sudden fatal PE and 174,115 (59%) followed undetected PE. Approximately two-thirds of symptomatic VTE events were hospital-acquired and one-third were community-acquired.
Conclusions Our study confirms that VTE is a major US health problem. Given that effective VTE prophylaxis and expert consensus prophylaxis guidelines are widely available, these data suggest that universal, safe and effective prophylaxis could significantly reduce US VTE incidence and related deaths. Future studies should address the impact of universal VTE prophylaxis on VTE incidence and survival.
Outcome of Patients &gt; Age 40 with Burkitt Lymphoma (BL) Treated with Aggressive Chemotherapuetic Regimens: Results from the International Burkitt Lymphoma Collaborative Group.
Authors: Friedberg Jonathan W. , Ciminello Lauren , Kelly Jennifer , Clawson Simon , Hoelzer Dieter , Holte Harald , LaCasce Ann S. , Mead Graham , Thomas Deborah , van Imhoff Gustaaf W. , Cheson Bruce , Magrath Ian T. , Fisher Richard I. 
Published: April 2020

Abstract
BL is considered a highly curable tumor when treated with dose-intensive, multiagent chemotherapy including central nervous system prophylaxis. 60–90% of pediatric and young adult patients (pts) with BL achieve durable remission if treated appropriately. However, the outcome of older adults with BL is more uncertain. We first investigated the SEER database and determined that 57% of reported pts with BL are &gt; age 40. We then performed a systematic review of published manuscripts describing outcome of adult pts (&gt; age 15) with confirmed de novo BL (REAL/WHO defined and confirmed) treated in the modern therapeutic era. Of 33 manuscripts, 17 were excluded due to small sample size (&lt; 10 pts), inclusion of pts with HIV, inclusion of pts with alternate histologies, or utilization of CHOP-like therapy. Corresponding authors of the remaining 16 manuscripts were contacted to provide details on outcome of pts &gt; age 40 for inclusion in a database, and full data is available from 12 manuscripts (10 prospective; 2 retrospective). 470 total adult BL pts ages 15–79 were treated, and 183 (39%) were &gt; age 40. Pts &gt; age 40 had significantly inferior outcomes in 10 of the 12 series. Treatment regimens included intensive short duration therapy (4 series; total N=212; &gt; 40 N=93); ALL-like therapy (6 series; total N=182; &gt; 40 N=62) and ASCT as part of induction therapy (2 series, total N=76; &gt; 40 N=28). The median overall survival at 2 years (OS) for all pts treated with short duration therapy was 71%, and for pts &gt; age 40 was 39%. The OS for all pts treated with ALL-like therapy was 51%, and for pts &gt; age 40 was 40%. Pts &gt; age 40 treated with ASCT as part of induction regimens had somewhat better outcomes (median OS 62%), however this represents a small number of pts who may have been subject to more rigorous selection criteria. We conclude that pts &gt; age 40 with BL are significantly underrepresented in the published clinical trials. Even when these pts are treated with appropriate intensive chemotherapy, the OS is inferior compared to published outcomes in younger pts, and is similar to OS survival historically observed with CHOP chemotherapy alone (40%). Future efforts should evaluate whether BL in older adults has unique biological features. Novel therapeutic regimens, with decreased toxicity, targeting the older majority pts with BL are required.
Primary Mediastinal Large B-Cell Lymphoma (PMBL) Outcome Is Significantly Improved by the Addition of Rituximab to Dose Adjusted (DA)-EPOCH and Overcomes the Need for Radiation.
Authors: Dunleavy Kieron , Pittaluga Stefania , Janik John , Grant Nicole , Steinberg Seth , Staudt Louis , Jaffe Elaine , Wilson Wyndham H. 
Published: April 2020

Abstract
Gene expression profiling has revealed that over one third of genes more highly expressed in PMBL than other DLBCLs are characteristically expressed in classical Hodgkin Lymphoma (HL) suggesting a biological relationship (J Exp Med198:851, 2003). PMBL and HL also share mediastinal presentation, young age, female predominance, prominent sclerosis and CD30 expression. Although some cases lie in a pathological “grey zone” between HL and PMBL, the latter is distinguished by robust CD20 expression. Like HL, local mediastinal failure after doxorubicin-based regimens has led to routine mediastinal xRT, which is associated with secondary malignancies and coronary disease. We analyzed the outcome of DA-EPOCH in 36 untreated PMBLs. No pts received xRT except for CNS PMBL. DA-EPOCH was administered with G-CSF for 2 cycles beyond CR for 6 to 8 cycles as described (Blood99:2685, 2002). The first 14 pts were on a DA-EPOCH study and the last 22 on a DA-EPOCH-Rituximab study. Most pts had adverse prognostic features with bulky disease, elevated LDH and extranodal sites, which were balanced among the 2 series. IHC in 34 cases was consistent with gene expression profiling of PMBL with frequent CD20+ 33/33 (100%), infrequent CD10+ 1/26 (4%) and variable BCL-6+ 17/24 (71%) and MUM-1+ 8/22 (36%) expression. Tumor proliferation by MIB-1 was high with a median (range) of 82% (54–98). IHC markers were similar among the 2 series. EFS and OS are shown below with a median follow-up of 8.6 and 3.4 yrs, respectively, for pts receiving DA-EPOCH −/+ R. Rituximab was associated with a significantly improved EFS (p=0.036) and trend in improved OS (p=0.10) by 2-tailed exact log-rank test. In conclusion, pt characteristics were consistent with the clinical-pathological and molecular definition of PMBL and prognostic features were similar to other series (Haematologica87:1258, 2002). These results suggest for the first time that rituximab significantly improves the outcome of PMBL and that DA-EPOCH-R obviates routine mediastinal xRT. DA-EPOCH-R may be more effective than CHOP-based treatment because it overcomes high tumor proliferation and employs pharmacodynamic dosing. Although needing confirmation, our results suggest DA-EPOCH-R without xRT is highly effective for PMBL. Patient Characteristics
Patient Characteristics Characteristics All Patients DA-EPOCH DA-EPOCH-R Total Patients 36 14 22 Gender (F/M) 23/13 (1.77) 9/5 (1.8) 14/8 (1.75) Median age, y (range) 33 (12–70) 34 (20–62) 33 (12–70) Median Mass cm (range) 8.9 (3–16) 8.4 (5.1–15.7) 10 (3–16) Bulky mass &gt; 6 cm 29 (83%) 11 (85%) 18 (82%) ECOG PS &gt; 1 4 (11%) 2 (14%) 2 (9%) Stage III or IV 15 (42%) 7 (50%) 8 (36%) LDH &gt; Normal 26 (72%) 12 (86%) 14 (64%) Extranodal sites 20 (56%) 7 (50%) 13 (59%) Pleural effusion 9 (25%) 3 (21%) 6 (27%) Figure Figure
Treatment of Post-Transplant Lymphoproliferative Disorder (PTLD) with Rituximab or Chemotherapy: The University of Pennsylvania Experience.
Authors: Elstrom Rebecca L. , Andreadis Charalambos , Aqui Nicole , Tsai Donald E. 
Published: April 2020

Abstract
Background: PTLD is a rare but life-threatening side effect of organ transplantation. While some patients respond to reduction in immunosuppression (RI), in many patients this approach is ineffective or impractical. Chemotherapy and anti-B cell monoclonal antibody therapy have been explored for treatment of such patients, but most reports include small numbers of patients. We report the results of treatment of patients with PTLD with rituximab and/or chemotherapy at the University of Pennsylvania Medical Center.
Methods: Data were collected using retrospective chart and database review. Patients were evaluated for baseline characteristics as well as response to therapy, time to treatment failure, and overall survival. Prognostic factors were identified by univariate analysis.
Results: 35 of 117 adult solid organ transplant patients diagnosed with PTLD that were refractory to RI underwent treatment with rituximab and/or chemotherapy. Median time to PTLD was 4 years (range 3 months to 23 years), and most patients presented with advanced stage (57%) and extranodal involvement (74%). 71% had elevated LDH. There were no significant baseline differences between patients receiving rituximab and those receiving chemotherapy. 22 patients underwent treatment with rituximab. The ORR was 68% (CR 59% and PR 9%). Median time to treatment failure (TTF) was not reached at median follow up of 19 months (range 0.8–51 months), and estimated OS was 31 months (1.5–51 months). EBV positivity was a favorable prognostic factor for achievement of response and TTF (p&lt;0.01). LDH elevation predicted shorter overall survival (0.04). No patient died due to rituximab toxicity, and all 8 patients who either did not respond or relapsed were able to undergo further treatment with chemotherapy. 23 patients received chemotherapy, 22 of whom were evaluable. ORR was 74% (CR 57% and PR 17%). At a median follow up of 27 months, median TTF was 10.5 months (0.4–54 months), and estimated OS was 42 months (0.4–70 months). Adverse prognostic factors for response included advanced stage (p=0.02), elevated LDH (p=0.01) and allograft involvement by tumor (p&lt;0.01). These factors, in addition to lack of achievement of CR, also predicted poor overall survival (p&lt;0.05 for all factors). 26% of patients receiving chemotherapy died due to treatment-related toxicity.
Conclusion: Rituximab and chemotherapy are effective treatments in patients with PTLD who fail or do not tolerate RI. While rituximab is generally well tolerated, chemotherapy is associated with marked toxicity. When possible, PTLD patients requiring therapy beyond RI should be considered for rituximab, especially those with EBV-positive disease. Chemotherapy should be reserved for those patients who fail rituximab, have EBV-negative tumors, or need a rapid response.
Genetic and Phenotypically Heterogeneity of Patients with Congenital Neutropenia.
Authors: Zeidler Cornelia , Schwinzer Beate , Bolyard Audrey A. , Pracht Gusal , Alter Blanche P. , Bonilla Mary A. , Cham Bonnie , Fier Carol , Freedman Melvin H. , Kannourakis George , Kinsey Sally , Boxer Lawrence , Dale David C. , Welte Karl 
Published: April 2020

Abstract
Severe congenital neutropenia (CN) is a general term for a group of disorders characterized by extremely low blood neutrophil counts (ANC &lt; 0.5 x 109 ), early stage maturation arrest of myelopoiesis, and recurrent bacterial infections. More than 90% of CN patients respond to daily G-CSF treatment with a sustained neutrophil increase associated with a significant reduction of infections and improved quality of life. However, prolonged survival unmasks an increased risk of leukemic transformation in some, but not all, subcategories of CN patients.
The Severe Chronic Neutropenia International Registry (SCNIR) has collected longitudinal data on on more than 400 patients with various causes of CN. This unique resource allows classification of different subtypes of CN and estimation of the relative frequency of these conditions. Our new classification scheme is as follows:
By inheritance - autosomal dominant severe congenital neutropenia (ADCN), autosomal recessive (ARCN, Kostmann syndrome), sporadic CN. By genetic aberrations - ELA2 related CN, SBDS related CN-(Shwachman-Diamond syndrome), G 4.5 on Xq28related neutropenia (Barth syndrome), CXCR4 related neutropenia (myelokathexis and WHIM syndrome). By clinical phenotype - associated symptoms (e. g. metabolic disorders, such as Shwachman-Diamond syndrome, glycogen storage disease 1b, Barth syndrome), G-CSF responsive or non-responsive CN, with or without G-CSF receptor mutations, with or without osteoporosis, or dysplastic features (e. g. organ abnormalities). By ethnic origin - e.g. CN in consanguineous Kurdish families, recessive neutropenia in Swedish family (Kostmann syndrome).
Recent research and the work of the SCNIR now permit a much improved classification of CN. The identification of subtypes of CN, their distinctive risks of malignant transformation, and their responses to treatment has contributed substantially to our general understanding of the problem of neutropenia. This knowledge also now allows clinicians to give patients and families much improved prognostic information and better guidelines for therapy.