bluuebunny/crossref_metadata_2025_split huggingface dataset:
Allogeneic Stem Cell Transplantation for Adult Acute Lymphoblastic Leukaemia: Local Results of Modern Transplant Practice.
Authors: Butler Jason P. , Kennedy Glen A. , Hill Geoff R. , Morton James , Western Robyn , Hutchins Cheryl , Durrant Simon 
Published: October 2019

Abstract
Aims: To report the single institution outcomes for recent allogeneic transplantation for adult acute lymphoblastic leukaemia (ALL), and explore variables predictive of successful outcome.
Methods: All patients with ALL transplanted at the Royal Brisbane Hospital between 1st January, 2000 and 31st December, 2005 were included in the study sample. Survival analysis was performed using the Kaplan-Meier product-limit method. Univariate and multivariate analyses were performed using Cox proportional hazards modelling. Follow-up was censored at 30th June, 2006.
Results: A total of 41 patients were included in the study cohort, including 28 males and 13 females. Median age at transplantation was 27.6 years (range 15.2 to 64.5). 34 patients had precursor-B phenotypes; the remaining 7 had T-lineage ALL. Based on cytogenetics, patients were high-risk (n=19), intermediate risk (n=12), good risk (n=2), or indeterminate due to inadequate diagnostic sampling (n=8). Patients were transplanted in CR1 (n=23, 2 patients demonstrating delayed CR), 1st relapse (n=5, 2 with early relapse, 1 with untested frank relapse, and 2 with refractory disease), CR2 (n=9, 2 with treated isolated CNS relapse), CR3 (n=1) and primary refractory disease (n=3). Conditioning regimen was CyTBI, with the exception of 1 patient who received fludarabine (125mg/m2) and cyclophosphamide (120mg/kg). All patients received cyclosporine and full-course methotrexate for GVHD prophylaxis. Donor source was matched sibling (n=17) and matched unrelated donor (n=24). 5 patients received unprimed bone marrow grafts; the remaining patients received peripheral blood stem cells. At a median follow-up for survivors of 1.8 years (range 0.5 to 6.4), overall and progression-free survival at 2 years is 61% (95% CI 43 to 75%) and 74% (95% CI 55 to 85%) respectively. 32 patients developed acute GVHD, of whom 27 (66%) developed Grades II–IV. 21/40 evaluable patients developed chronic GVHD; all were extensive stage. 9 patients relapsed during follow-up at a median of 0.47 years post transplant (range 0.02 to 1.46); 1 remains alive in remission following reinduction therapy. 6 patients died from therapy-related causes - 3 from pulmonary toxicity, and 1 each from fungal sepsis, leukoencephalopathy, and hepatic GVHD. On both univariate and multivariate analyses of overall survival, younger age, transplantation in CR1, and development of chronic GVHD were predictors for an improved outcome.
Conclusions: Allogeneic stem cell transplantation for ALL is associated with excellent long-term outcome with respect to both disease control and treatment related toxicity. From these data, transplantation in CR1, younger age, and the development of chronic GVHD are covariates associated with prolongation of overall survival.
Febrile Neutropenia in Lymphoma Patients Is Associated with Substantial Resource Use and Healthcare Costs in Clinical Practice in Spain.
Authors: López A. , Alonso J.D. , Gómez-Codina J. , Novo A. , Herrera C. , Lara N. , Gasquet J.A. , Sánchez J. ,   on Behalf of the ENIA Study Group
Published: October 2019

Abstract
Background
Despite the significant impact of chemotherapy-induced febrile neutropenia (FN) on patients (pts) with cancer and its consequences for health care costs, there have been no studies in common clinical practice in Spain assessing the burden and economic impact of this complication.
Methods
This is a sub-analysis of lymphoma pts included in a multicentre, retrospective, chart review of adult pts from 16 Spanish hospitals who suffered from at least one FN episode related to cytotoxic chemotherapy (CT). Resource use and subsequent costs including days of hospitalization, number of transfusions, number and type of complementary tests, use of colony-stimulating factors (CSFs), and use of antibiotics and other drugs to manage FN were assessed for each episode. The impact of FN on planned CT was also analysed in terms of dose delays (DD) and/or reductions (DR).
Results
Medical charts from 194 pts were reviewed, 67 (34.5%) of whom had lymphoma, which accounted for 87 documented FN episodes included in this analysis. The median (range) age of patients was 62 (19–85) years, 31.7% had aggressive NHL, and 58.2% were treated with CHOP-like CT. FN appeared during first CT cycle in 61.2% of the pts. Hospitalization was required in 100% of the pts and the median length of hospital stay due to FN was 8 days (p25:6–p75:11). During an FN episode, 42% of pts required ≥1 transfusion, 100% needed a blood test and 98.9% a blood culture. Microbiologically documented infection appeared in 33% of FN episodes. All pts were treated with antibiotics (69.3% with cephalosporins) and CSFs were used in 64.8% of pts. In 40.9% of episodes, FN impacted on planned CT dose and/or schedule: DR was observed in 16.7% of pts, DD in 24.0% and CT withdrawal in 15.2%.
Conclusions
FN has a substantial impact on resource use and associated costs in pts with lymphoma. Hospitalization and antibiotic treatment were the main drivers of the cost associated with the management of FN in current clinical practice. Furthermore, FN has a meaningful effect on planned CT dose and/or schedule, with potential consequences for treatment outcome.
Mean (SD) healthcare costs per FN episode (All cost data expressed as €) Hospitalization Transfusions Complementary Tests CSFs Antibiotics and Other Drugs Total 3,557.17 (3,050.44) 43.24 (58.59) 162.77 (135.36) 223.39(231.40) 527.67 (448.56) 4,514.24 (3,392.20)
In Vivo Studies of Autologous Platelets Stored at Room Temperature (22°C), 4°C, and 4°C with Galactosylation.
Authors: Slichter Sherrill J. , Wandall Hans H. , Hoffmeister Karin M. 
Published: October 2019

Abstract
Background: Previous studies in a mouse model with “chilled” mouse platelets stored at 4°C for two hours with and without galactosylation showed protection against the adverse effects of chilling with galactosylation (Science2003;301:1531). However, prior studies with human platelets demonstrated that the adverse effects of 4°C storage became irreversible only after 18 to 24 hours of 4°C storage (J Lab Med1978;6:971). Therefore, we performed viability studies using human platelets stored for two days to exceed the period of potential reversibility of any cold-induced platelet injury.
Methods: Apheresis platelets were collected using Haemonetics MCS+ equipment from four normal volunteers. After collection, the platelets were pooled into one bag, and then the platelets were divided equally between two storage bags. Half of the platelets from each of the four collections were stored at 4°C with galactosylation, and the other half of the platelets were stored at 4°C without galactosylation (two collections) or at 22°C using standard storage conditions (two collections). After storage, samples from each of the two types of platelets stored from a volunteer were radiolabeled with either 51Cr or 111In, re-injected, and serial blood samples were drawn to determine post-transfusion recoveries and survivals of the radiolabeled autologous platelets.
Results: Results of the radiolabeled platelet studies are shown in the table.
In Vivo Radiolabeled Autologous Platelet Recoveries And Survivals 4°C GALACTOSYLATED PLATELETS 4°C STORED PLATELETS 22°C STORED PLATELETS Normal Volunteer Recovery (%) Survival (Days) Recovery (%) Survival (Days) Recovery (%) Survival (Days) 1 46 2.8 48 2.9 2 64 2.8 58 2.8 3 46 2.2 59 6.8 4 26 1.0 34 6.9 Ave. ± 1 S.D. 46 ± 16 2.2 ± 0.9 53 ± 5 2.9 ± 0.1 47 ± 13 6.9 ± 0.1
No adverse events were reported with the transfusion of the galactosylated platelets, there was no evidence of the development of anti-platelet antibodies against galactosylated or non-galactosylated platelets, and samples of the galactosylated platelets obtained after storage verified galactosylation of the platelets.
Conclusions: The data show that, following two days of 4°C storage, the recoveries and survivals of the galactosylated platelets are no different than the non-galactosylated 4°C stored platelets from the same volunteer. Although the recoveries of the 4°C stored platelets with and without galactosylation are well-maintained compared to the 22°C stored platelets, the survivals are markedly reduced as has been previously shown for 4°C stored platelets (Br J Haematol1976;34:403).
A Randomized, Double-Blind, Placebo-Controlled Trial of Thalidomide Plus Dexamethasone Versus Dexamethasone Alone as Primary Therapy for Newly Diagnosed Multiple Myeloma.
Authors: Rajkumar S. Vincent , Hussein Mohamad , Catalano John , Jedrzejcak Wieslaw , Sirkovich Svetlana , Olesnyckyj Marta , Yu Zhinuan , Knight Robert , Zeldis Jerry , Blade Joan 
Published: October 2019

Abstract
Purpose: Updated results, including response rate data, from a randomized, double-blind, placebo-controlled study comparing thalidomide plus dexamethasone versus dexamethasone alone as primary therapy for newly diagnosed multiple myeloma (MM).
Methods: Patients (pts) with previously untreated, symptomatic MM were eligible. Pts were randomized to Thal/Dex (Arm A) or placebo plus Dex (Arm B). Pts in Arm A received Thal 50 mg PO daily, escalated to 100 mg on day 15, and to 200 mg from day 1 of cycle 2; Dex 40 mg PO was given on days 1–4, 9–12, and 17–20. Pts in Arm B received placebo instead of Thal, and Dex as in Arm A. Each cycles was 28 days long. Treatment was continued until progression or undue toxicity. The primary endpoint was time to progression (TTP) defined using EBMT criteria. All analyses were conducted on an intent to treat basis. An independent data monitoring committee recommended release of results.
Results: 470 pts were enrolled: 235 were randomized to Thal/Dex and 235 to placebo/Dex. Median follow up is 18 months. Median age was 65 yrs. The response rate (CR+PR) was significantly higher with Thal/Dex compared to placebo/Dex, 59% vs 42%, respectively, P<0.001. Eighty-two percent of patients have gone off-study. TTP was significantly superior with Thal/Dex vs placebo/Dex, median TTP not reached with Thal/Dex versus 8.1 months (95% CI: 6.5–12.8 months) with placebo/Dex, P<0.001. Major grade 3–4 events are summarized in the Table below. Deep vein thrombosis (DVT) was higher with Thal/Dex vs placebo/Dex, 15.4% vs 4.3%, respectively.
Conclusions: Thal/Dex yields superior response rates and TTP compared to Dex alone when used as first-line therapy for multiple myeloma.
Major Grade 3–4 adverse events Adverse Event Thal/Dex (n=234) Placebo/Dex (n=232) Venous thromboembolism (Grade >=3) 17.9% 4.3% Cerebral ischemia (Grade >=3) 3.0% 1.3% Myocardial ischemia (Grade >=3) 3.8% 2.2% Neuropathy (Grade >=3) 3.0% 0% Any toxicity (Grade >=4) 30.3% 22.8%
Tendency towards Minor Bleeding in Women Is Associated with a Reduced Risk for Major Bleeding, without Apparent Differences in Level of Anticoagulation during Treatment with Vitamin K Antagonist.
Authors: Veeger Nic J.G.M. , Piersma-Wichers Margriet , van der Meer Jan 
Published: October 2019

Abstract
Easy bruising is frequently found in healthy women. This mild bleeding tendency may be enhanced by treatment with vitamin K antagonists. This may result in more intense monitoring of the level of anticoagulation (INR) to improve the individual time within target range (ITTR) and consequently to reduce the risk of major bleeding. We performed a retrospective study in 6758 consecutive patients receiving vitamin K antagonists for primary or secondary prophylaxis of venous or arterial thrombosis (mean age 67, 51% male and 189762 INRs in 6681 person-years) to evaluate differences in gender on the occurrence of minor and major bleeding, as well as the ITTR.
The incidence rates (IR, per 100 person-years) of minor and major bleeding were assessed and survival analysis performed to obtain adjusted hazard ratios (HR, 95%CI) for major bleeding in men versus women with or without prior minor bleeding, controlling for significant patient characteristics. Minor bleeding occurred more frequently in women than men (IR=33.2 versus 21.1, respectively; HR=1.5, 95%CI 1.4–1.7, p<0.001), whereas major bleeding showed a tendency towards a higher incidence in men (IR=1.6 versus 2.0; HR=1.3, 95%CI 0.9–1.8, p=0.20).
Figure Figure
However, in women with prior minor bleeding, the incidence of major bleeding was low (IR=1.3, 95% CI 0.7–2.1), when compared to men with minor bleeding (3.3, 95%C 2.2–4.7) (HR =2.7, 95% CI 1.4–5.0, p=0.002). Men and women without prior minor bleeding had comparable incidences of major bleeding (IR 1.8, 95% CI 1.3–2.5, and 1.5, 95% CI 1.1–2.1, respectively), but both were higher than in women with prior minor bleeding (HR 1.4 (0.8–2.5, p=0.30 and 1.2 (0.7–2.2, p=0.55)). These differences were even more pronounced in patients at high risk of major bleeding due to a strongly reduced ITTR (ITTR below 30%, lowest quartile).
Considering the actually achieved level of anticoagulation, there were no differences between men and women with or without prior minor bleeding that could explain the reduced risk of major bleeding in women with prior minor bleeding. With 42% to 43%, the ITTR was comparable, as was the time spend above INR 5.0 (6% to 7%).
In conclusion, more frequent minor bleeding in women was associated with a reduced incidence of major bleeding, whereas in men, such a reversed association was not present. Differences in intensity of INR monitoring in patients with or without minor bleeding and as a result in actual level of anticoagulation, could not be demonstrated.
Liquid Heparin Assay: A Straightforward Approach for Monitoring the Clinical Use of Heparins.
Authors: Kung Chun , Gabbeta Jagadeesh , Krougliak Valeri , Quiazon Emmanuel , Triscott Mark 
Published: October 2019

Abstract
There are number of commercial heparins available in the market. The choice of heparin may depend on the clinical condition of the patient. For example, patients with deep-vein thrombosis (DVT), low molecular weight heparins (LMWH) (such as enoxaparin) may be used; whereas for pulmonary embolism (PE) cases, unfractionated heparins (UFH) may be the heparin of choice. In clinical studies, the synthetic heparin pentasaccharide, Fondaparinux (commercially known as Arixtra) has been shown to be efficacious in the treatment of both types of patients. Monitoring heparin activity in patients under treatment is critical in reducing the patient risk of bleeding or thromboembolism. The majority of current available tests allow measurement of heparins in the range of 0.0 – 1.0 U/mL. In many clinical laboratories, the analysis of each type of heparin requires a separate calibration curve, which makes the assay more complex and time consuming. In most cases these calibrators are “home made” and are not related to a standard, which may contribute to variability in testing. The reagents are usually provided in lyophilized form and require prior reconstitution which can introduce additional variation and increase handling time. An assay developed here, based on ready to use liquid reagents and designed for use on ACL TOP™, ACL Futura®/, ACL Advance™ ACL Elite™/ACL Elite Pro™ and ACL™ 9000/10000, addresses these issues and minimizes testing time. The Liquid Heparin Assay is built on the one stage principle of heparin detection, utilizing endogenous antithrombin III. The assay kit consists of two reagents, a liquid Factor Xa and a chromogenic substrate for Factor Xa, S2732. The composition of the kit and assay parameters are optimized to achieve overlay of the calibration curves for UFH and LMWH in the range from 0.0 to 2.0 U/mL of heparin activity. Furthermore, the assay is evaluated with respect to the various commercial heparins including Enoxaparin, Fragmin and Arixtra. The calibration curves for WHO UFH standard, WHO LMWH standard, Enoxaparin, and Fragmin are observed to overlap, with a maximum difference of 10% at each calibration point. The recoveries of heparin activities in samples spiked with various heparins are also within 10% of the expected values. The weight concentration (μg/mL) of Arixtra in plasma samples and its corresponding heparin activity (U/mL) can also be measured using this assay. The potential utility of the Universal Calibrator, composed of the mixture of UFH and LMWH is also evaluated and shown to be promising. Thus, the Liquid Heparin Assay permits simultaneous determination of various commonly used heparins in patient samples using a single calibration curve, and ready to use reagents. This can simplify analysis, reduce time and improve assay reliability. Since one assay is sufficient to measure different heparins, this assay could also reduce the overall costs of heparin analysis in the clinical laboratory.
Successful Overcoming of Imatinib Resistance by Synergistic Effect of Imatinib and Simvastatin in Imatinib Resistant Chronic Myelogenous Leukemia Cell Line.
Authors: Oh Bora , Kim Tae Young , Min Hyun Jung , Yoon Sung-Soo , Lee Dong Soon 
Published: October 2019

Abstract
Statins (HMG-CoA reductase inhibitors) are known to show antiproliferative effects and are anticipated as a potential drug in the treatment of malignancies including acute myelogenous leukemia (AML) and multiple myeloma (MM). Using cell proliferation assays, we determined the effects of simvastatin in CML cells. In the current study we show that simvastatin inhibits the proliferation of CML cell lines (The IC50 to simvastatin of K562, Kcl22, and LAMA84 were 13 uM, 19 uM, and 31 uM, respectively). Moreover, synergistic interactions between simvastatin and imatinib were observed in imatinib-resistant CML cell lines (K562-r, KCL22-r, and LAMA84-r). The cytotoxic effect of simvastatin occurred via the induction of apoptosis and inhibited Bcr-Abl tyrosine kinase (TK) activity, as evidenced by annexin V assay and Western blot analyses. Co-treatment with imatinib and simvastatin decreased the amount of Bcr-Abl protein and stimulated the import of Abl protein in the nuclei in K562 cells. Simvastatin may be a potential candidate for the treatment of imatinib-resistant CML patients and the effective dose of imatinib could be reduced in a combined treatment with simvastatin. Mean combination index (CI) values at 50%, 75%, and 90% growth inhibition (IC50, IC80) derived from combined treatment experiments
Cell line Drug combination Drug ratio CI: IC50 CI: IC75 CI: IC90 Gradual levels of synergy are marked as recommended by the manufacture of the Calcusyn software: +++, strong synergism; ++, moderate synergism; + slight synergism; ±, nearly additive; −, slight antagonism: and − −, moderate antagonism K562-s Imatinib + Simvastatin 1:40 0.61+++ 0.49+++ 0.40+++ K562-r Imatinib + Simvastatin 1:10 0.60+++ 0.46+++ 0.41+++ Kcl22-s Imatinib + Simvastatin 1:100 0.96± 1.32− 1.83− − Kcl22-r Imatinib + Simvastatin 1:1 0.42+++ 0.35+++ 0.30+++ LAMA84-s Imatinib + Simvastatin 1:200 1.20− 1.0± 1.0± LAMA84-r Imatinib + Simvastatin 1:20 0.99± 0.8+ 0.84+ Figure Figure
Detection of the V617F Mutation of JAK2 Using a Novel Fully Automated SNP Super-Rapid Detector.
Authors: Tanaka Ruriko , Kuroda Junya , Ashihara Eishi , Ishikawa Takayuki , Taki Tomohiko , Hirai Mitsuharu , Majima Satoshi , Taniwaki Masafumi , Maekawa Taira , Kimura Shinya 
Published: October 2019

Abstract
The JAK2 V617F substitution mutation (JAK2V617F) is one of the genetic hallmarks of chronic myeloproliferative diseases (CMPDs), such as polycythemia vera (PV), essential thrombocythemia (ET), or chronic idiopathic myelofibrosis (CIMF). Accurate and rapid detection of this mutation is essential for diagnosing and treating CMPDs today. We have developed a novel, rapid, sensitive and fully-automated single nucleotide polymorphism (SNP) detection system, termed ARKRAY SNP Detection System (ASDS), and used it to detect JAK2V617F in patients with CMPDs. With ASDS, diagnosis requires only 100ml of whole blood (or DNA), and the system automatically performs DNA extraction and PCR. The detection of both wild type and mutant jak2 alleles from PCR amplicons was measured by the increase in fluorescence produced by the dissociation of a JAK2V617F-specific guanine-quenching probe, and was completed within 75 minutes. In dilution assays of HEL cells (a JAK2V617F-positive leukemia cell line) using MYL cells (a chronic myelogenous leukemia (CML)-derived cell line with wild type JAK2), the system reliably quantified the mutation in a cell population containing as few as 1.0% mutant cells (Figure). We tested 44 samples from CMPDs patients using ASDS and direct sequencing (DS) (13 PV, 23 ET, 3 CIMF, 1 chronic myelomonocytic leukemia (CMMoL), 1 chronic neutrophilic leukemia (CNL), 3 unclassifiable CMPD (uCMPD)), which included samples from 3 post-allogenic bone marrow transplantation (BMT) patients with CIMF or uCMPD. Using ASDS, we detected JAK2V617F in 12/13 PV, 13/23 ET, 0/1 CIMF without BMT, 1/1 CMMoL, 0/1 CNL and 1/3 uCMPD. Overall, these results were comparable to previous results using relatively sensitive detection strategies, such as allele-specific PCR (AS-PCR). One of the 3 post-BMT CIMF samples was positive for JAK2V617F, which indicated that there were residual disease clones after BMT. ASDS detected JAK2V617F in one PV and eight ET patients, while DS failed to detect the mutation in these same samples, which clearly indicated that ASDS has a higher sensitivity than DS. JAK2V617F was absent in all samples from secondary erythrocytemia and healthy volunteers. Collectively, these results demonstrate that ASDS is a powerful and convenient tool for detecting JAK2V617F. With its associated high sensitivity, convenience and rapidity, this system will enable “Point-of-care” testing in clinical laboratories and “Patient-oriented” therapy for CMPDs. ASDS could also be applied to the detection of other point mutations relevant to cancer treatment, such as mutations in the BCR-ABL kinase domain that are associated with CML.
Figure Figure
Serum Free Light Chain Assessment in 311 Patients with Gammopathy.
Authors: Trigo Fernanda , Guimaraes Cristina , Bodas Abilia , Teixeira-Pinto Armando , Guimaraes Jose E. 
Published: October 2019

Abstract
Serum free light chain (FLC) levels are a useful multiple myeloma (MM) marker and a indicator of tumour burden both for diagnosis and follow up purposes. A total of 311 patient samples were assayed in our laboratory for FLC and the kappa/lambda (κ/λ) chain ratio was calculated and compared with the classical methods for characterization of gammopathy (immunofixation, IMF, immunoglobulin levels and total light chain levels and respective ratio). Ig (A, G, M) and total κ and λ chain levels were assayed by nephlometry (Dade-Behring BNII). Immunofixation was performed in a Hydrasys (Sebia) setting. FLC assay was done using Binding Site reagents (Dade-Behring). Statistical analysis was performed by SPSS® for Windows v. 15. Concordance between IMF results and free κ/λ chain ratio was calculated. Sensitivity and specificity of the free κ/λ chain ratio in the identification of positive and negative IMF were also determined. Reference intervals used for free κ/λ and total κ/λ chain ratios were [0.26; 1.65] and [1.35; 2.65], respectively. Out of 311 patients with gammopathy studied, 235 had absence of monoclonality as defined by the immunoelectrophoretic profile. Inclusively, only 51% of the 53 patients with suspected MM and 66% of the 41 patients with a diagnosis of MGUS were IMF positive. Sensitivity and specificity of total κ/λ chain ratio for identification of positive or negative IMF were respectively 70% and 91% with a global concordance of 86%. In 215 (70%) patients, IMF and free κ/λ chain ratio were in agreement. However, 74 (32%) of IMF negative patients had abnormal free κ/λ chain ratio: 18% had a final diagnosis of chronic renal failure, 13% of CLL or NHL, 9% of MGUS, 7% of MM and 3% of amyloidosis; the remainder 50% were diagnosed as having a disease other than lymphoplasmacytic disorder. These results stress the value of free light chain determination in the diagnosis and follow up of gammopathies and its usefulness as a marker for multiple myeloma and associated monoclonal gammopathies.