bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intensified CHOP with Rituximab for Intermediate or High-Risk Non-Hodgkin’s Lymphoma: Interim Analysis of a Randomized Phase III Trial in Elderly Patients by the Dutch HOVON and Nordic Lymphoma Groups.
Authors: Sonneveld Pieter , van Putten Wim , Holte Harald , Biesma Douwe , van Marwijk-Kooy Marinus , Kramer Mark , Wijermans Pierre , Steijaert Monique , Huijgens Peter , Eriksson Mikael 
Published: April 2020

Abstract
High-risk Non-Hodgkin lymphoma (NHL) in elderly patients (&gt; 60 yrs) is associated with a relatively low complete response (CR) rate and a poor overall survival (OS). Previous studies have shown that addition of Rituximab to standard CHOP chemotherapy may improve CR and/or OS. A similar improvement has been shown for intensification of CHOP from 21 day intervals to 14 day intervals. The Dutch HOVON group and the Nordic lymphoma group have performed a multi-center, randomized phase III trial to compare 8 cycles of intensified CHOP (CHOP14) with the same regimen plus 6 administrations of Rituximab in previously untreated elderly patients with intermediate or high-risk NHL. Inclusion criteria were diffuse large B-cell lymphoma, mantle cell lymphoma or follicular lymphoma grade III; intermediate or high-risk NHL according to age adjusted IPI score; CD20-positive NHL; age 65 yrs or higher. The target number was 400 patients to be accrued in 5 years based on an expected increase in event-free survival with hazard ratio HR=0.70.
Aplanned interim analysis was performed after inclusion of 250 patients, restricted to 211 patients included from 1st September 2001 to 1st October 2004. Forty patients had to be excluded because of lack of treatment and evaluation data, leaving 171 patients for the analysis. The median time off protocol treatment was 119 days (range 4–468 days). The median age was 73 years (range 62–88 years). There was no difference between the two treatment arms regarding histology, age, WHO classification of NHL, age-adjusted IPI score, Ann Arbor stage, WHO performance status and serum LDH. There was no significant difference of toxicity or CR between the two treatment arms. However, a highly significant difference was observed for event-free survival and overall survival in favor of the treatment arm with CHOP plus Rituximab. Based on this interim analysis, the randomization was halted and patients in the control arm were further treated with CHOP plus Rituximab. Since the outcome of the interim analysis could be biased due to incomplete data, a final decision to stop the trial awaits a new analysis which is planned for 26th August 2005 after collection of missing or incomplete data. If the new analysis confirms the results of the interim analysis, i.e. that Rituximab significantly improves the outcome of treatment in elderly patients with intermediate or high-risk NHL, even when an intensified CHOP regimen is used, the study will be closed and outcomes will be presented.
The Role of Oxidative Stress on Telomere Shortening, Telomere Dysfunction and Damage to Telomere G- Strand Overhang - A Putative Model of Carcinogenesis in Fanconi Anemia Cells.
Authors: Lahav Meir , Uziel Orit , Reshef Hagai , Ravid Anat , Fabian Ina 
Published: April 2020

Abstract
Fanconi Anemia is an autosomal recessive disease characterized by various inborn abnormalities and severe genetic instability, which may lead to bone marrow failure and increased incidence of cancer. One possible explanation for this genomic instability may be the cellular hypersensitivity to oxidative stress, leading to chromosomal breaks. The goal of our study was to explore the possible oxidative damage caused by H2O2 to telomeres of Fanconi Anemia (FA) lymphocyte cell line, HSC536/N and its possible relation to carcinogenesis. We surmised that combination of oxygenative damage to telomere function with Overexpression of telomerase may provide a model for malignant transformation in those cells.
The cells were grown in the presence of hTR anti-sense (GRN163) and exposed for one month to hydrogen peroxide combined with a variety of antioxidants. One month of exposure caused marked shortening of telomere (TRF) length (measured by Southern blot), and damage to the single stranded overhang of the telomere [using the newly developed telomeres oligonucleotide ligation assay (T-OLA)]. The telomere and single stranded overhang shortening was associated with significant telomere dysfunction (assessed by karyotype analysis). Control cells did not exhibit this sensitivity to H2O2. Telomere dysfunction did not evoke damage response in FA cells, in contrast to normal p53 up regulation in control cells. Reconstitution of telomerase activity protected FA telomeres from further oxygenative damage. Several antioxidants prevented the H2O2 exerted damage. Based on our data we suggest a model of malignant transformation in FA in which oxidative stress led to a significant shortening of the overall length of the telomere and the single stranded overhang, thus causing telomere dysfunction. P53 mediated damage control was absent in these cells, preventing apoptosis or cycle arrest. Reconstitution of telomerase activity further stabilizes the damaged telomeres preventing crisis and forming the basis for future carcinogenesis. The differential effects of the antioxidants and the significance of our findings to malignancies will be discussed.
Novel Risk Factors for Venous Thromboembolism (VTE): A Population-Based Case-Control Study.
Authors: Heit John A. , Farmer Sara A. , Petterson Tanya M. , Bailey Kent R. , Melton L. Joseph 
Published: April 2020

Abstract
Background: While several uncommon disorders (e.g., myeloproliferative diseases, connective tissue disease, etc.) have been suggested as potential risk factors for VTE, the independence and magnitude of any risk is uncertain.
Objective: To test uncommon characteristics as potential independent risk factors for VTE, and estimate the magnitude of risk for each.
Methods: Using the resources of the Rochester Epidemiology Project, we identified all incident cases of deep vein thrombosis and pulmonary embolism over the 6-year period, 1992–1997. For each objectively confirmed case (n=562), we identified up to two Olmsted County residents without VTE who most closely matched a case on age, gender, and medical record number (n=755). Because medical record numbers are assigned sequentially, such matching assures a similar duration of medical follow-up. For all cases and controls, we reviewed the complete medical records in the community for over 125 baseline characteristics which were tested for an association with VTE using conditional logistic regression.
Results: The mean ± SD (range) ages for cases and controls were 65.71 ± 18.85 (0–102) and 64.90 ± 18.66 (0–102) years, respectively, and 55.5% were female. Novel univariate risk factors for incident VTE included former tobacco smoker, ischemic heart disease, valvular heart disease, chronic lung disease, all-cause pulmonary hypertension, chronic renal disease, myeloproliferative disorders, any infection, femoral artery catheterization (angiography or percutaneous intervention), ICU admission and angiotensin converting enzyme (ACE) inhibitor therapy. Among infections, septicemia, pneumonia, and ENT, cardiovascular, GI, urinary tract and skin/soft tissue infections were univariately associated with VTE; reproductive tract infection was not. Diabetes mellitus, hyperlipidemia, lipid-lowering drugs (including statins), inflammatory bowel disease, asthma, connective tissue disease, and influenza were not univariately associated with VTE, and beta-blocker therapy was not protective. A multivariate analysis will test these characteristics as potential independent VTE risk factors.
Conclusions: Several novel characteristics are univariately associated with VTE. Such novel characteristics may provide new insights into VTE mechanisms if, upon further analysis, these characteristics are independent VTE risk factors.
Rates of Clinically Apparent Venous Thromboembolism and Death Resulting from Pulmonary Embolism among Unselected Hospitalized Acutely Ill Medical Patients Versus Rates Predicted from Clinical Studies.
Authors: Piovella Franco , Anderson Frederick A. , Decousus Hervé , FitzGerald Gordon , Bergmann Jean-François , Kakkar Ajay K. , Spyropoulos Alex C. , Zotz Rainer B. , Spencer Frederick A. , Turpie Alexander G.G. ,   for the IMPROVE Investigators
Published: April 2020

Abstract
Background
Without evidence from autopsies, the majority of deaths resulting from pulmonary emboli (PE) are indistinguishable from deaths due to other cardiovascular diseases. This has led to a gap in perceptions between the benefits and risks of providing venous thromboembolism (VTE) prophylaxis. In this study, we estimated the incidence of clinically apparent VTE in hospitalized acutely ill medical patients in The International Medical Prevention Registry on Venous Thromboembolism (IMPROVE), and compared this with the expected incidence derived from clinical studies that used autopsy or prospective venographic confirmation of clinically important VTE.
Methods
Beginning in July 2002, a consecutive, unselected sample of patients who were aged ≥18 years and hospitalized for ≥3 days with an acute medical illness, were enrolled in this observational cohort from 49 hospitals in 12 countries. Up to 31 March 2005, 6946 patients were enrolled.
Results
Based on autopsy series of all-cause in-hospital deaths reported in the literature, PE is associated with 10% of deaths, is the primary cause in 5%, and is clinically recognized as the primary cause in 1.5% of deaths. A review of clinical studies with mandatory venography resulted in predicted rates of 10% for all VTE and 1% for clinically recognized (confirmed) VTE. In IMPROVE, there were 4/291 (1.4%) deaths due to clinically recognized PE (vs. 4 predicted). There were 79 (1.1%) treated VTE events (vs. 69 predicted).
Conclusions
Observed rates of death due to PE and clinically recognized VTE in a real-world setting are consistent with predictions from clinical study data. Physicians should be aware of the significant gap that exists between clinically important and clinically evident VTE events. Reliance on the low rates of clinically recognized events to assess the seriousness of this disease can lead to a significant under-estimation of its impact on public health and a consequent failure to realize the proven benefits of VTE prophylaxis in hospitalized acutely ill medical patients.
The Risk of Dialysis Access Thrombosis Is Related to Polymorphisms in the Transforming Growth Factor-β1 and Plasminogen Activator Inhibitor-Type 1 Genes.
Authors: Lazo-Langner Alejandro , Knoll Greg A. , Wells Philip S. , Pilkey Rachel M. , Carson Nancy , Rodger Marc A. 
Published: April 2020

Abstract
Background. Transforming growth factor-β1 (TGF-β1) is involved in cell growth and differentiation and it plays an important role in the genesis of fibrosis through the stimulation of neointima proliferation and accumulation of components of the extracellular matrix and it has been suggested that polymorphisms (polym) in its gene contribute to determining the patency of the vascular access (VA) in patients (pts) on hemodialysis (HD) by contributing to both atherogenesis and VA thrombosis. On the other hand it has been demonstrated that polym in the gene encoding the plasminogen activator inhibitor type-1 (PAI-1) are a risk factor for ischemic heart disease and possibly stroke although their role in other vascular territories is unknown. It is also known that TGF-β1 is an important up-regulator of the PAI-1 gene.
Methods. We conducted a case-control study to determine the relationship between TGF-β1 polym of the signal sequence (869 T&gt;C; 915 G&gt;C) and VA thrombosis in 416 HD pts. (107 with VA thrombosis, 309 controls had no thrombosis). We also explored for possible interactions with the 4G/5G polym of the PAI-1 gene. TGF-β1 and PAI-1 polym were amplified using PCR and genotyped using an ABI PRISM 3100 Genetic Analyzer. TGF-β1 producing haplotypes (haplo) were defined as low, intermediate or high as previously reported. All pts were also tested for thrombophilia. Statistical analysis was done using univariate and multivariate logistic regression adjusted for thrombophilia, age, access type, etc.
Results. Frequencies for low, intermediate and high TGF-β1 producing haplo were 9.3, 26.2 and 64.5% in cases and 2.6, 22.3 and 75.1% in controls.
Odds of thrombosis for TGF-β1 haplotypes Haplotype Crude OR (95% CI) p Adjusted OR (95% CI) p High producing haplotype is reference category Low 5.11 (1.93, 13.5) 0.001 7.31 (2.15, 24.88) 0.001 Intermediate 1.30 (0.74, 2.29) 0.36 1.39 (0.70, 2.75) 0.35
Figure Figure
Frequencies for 5G/5G, 4G/5G and 4G/4G PAI-1 polym. were 21.5, 56.1 and 22.4% in cases and 25.6, 50.2 and 24.3% in controls respectively. When we explored the interaction between both gene polym we found a highly significant result for the interaction between the low TGF-β1 producers and the 4G/4G PAI-1 polym (adjusted OR 19.3; 95% CI 2.82, 132.40; p=0.003).
Conclusions. Our results show that intermediate and high producing TGF-β1 haplo have a protective effect against VA thrombosis in HD patients that is not modified by PAI-1 polym and also suggest that the interaction between low TGF-β1 producing haplo and the 4G/4G PAI-1 polym might be an important contributor to thrombosis of the VA in HD pts. Further studies are ongoing to determine the relationship between TGF-β1 haplo, TGF-β1 level, and PAI-1 polym with thrombosis in this and other populations as well as to clarify the mechanisms underlying this apparently paradoxical effect.
Prevalence and Clinical Significance of Single and Combined Inherited Thrombophilias.
Authors: Losonczy Hajna , Nagy Agnes , Toth Orsolya , Balassa Katalin , David Marianna , Kecskes Marianna , Vidra Timea , Szomor Arpad 
Published: April 2020

Abstract
The prevalence of inherited single and combined thrombophilias were examined in 986 patients (330 males and 656 females) between 1995–2004 with venous thromboembolism (VTE).
Methods: Screening blood coagulation tests (PT, APTT, TT, FG), coagulation inhibitor activities and antigen levels (AT, PC, PS), APC-R, FV: Q506, FII 20210A, anti-phospholipoid antibodies, plasma homocystein level and circumstantial risk factors were examined. The age at first thromboembolic episode, family history for thrombosis, localization of VTE, therapies administered, recurrences, chronic venous insufficiency (CVI) and crural ulcer (CU) were registered.
Results: The mean age at the first thromboembolic episode was 34,4 +/− 11,4 y. VTE was present in the family in 416 cases (46%), the mean observation time was 9,24+/−8,81 years. We found AT deficiency in 4,3%, PC in 5,9 % (mutation in the PC gene was verified in 7 families), PS in 5,4%. APC resistence was 25,3%, FV:Q506 mutation 24%. Inherited defect was present in 459 p. (46,5%). Single inherited abnormality in 279/986 p. (28,2%), combined in 82/986 p. (8,3%), two abnormalities in 70, three in 11 and four in 1 patient. The distribution of circumstantial risk factors among patients with and without inherited coagulation abnormalities were equal, except OC usage, pregnancy and labor. These obstetrical risk factors occured significantly higher in patients having inherited abnormalities. VTE in the family, the ileofemoral localization of the VTE and the need for thrombolythic therapy was also significantly higher among patients with inherited abnormalities. We also examined and compared the occurence rate of recurrence, CVI and CU among patients with single and combined inherited abnormalities vs. those without such abnormalities. Recurrence rate was significantly higher in patients with coagulation defects vs. without defects, and between those having only one vs. more defects. It was not dependent on the type of the single coagulation defect. FVQ506+PC and FVQ506+AT defects increased, whereas the FVQ506+FII20210A and +PS defects did not increase singificantly the relapse rate. The occurance of CVI and CU in patients with coagulation defects was significantly increased independently of having one vs. more defects.
Conclusions: Inherited coagulation abnormalities predisposing to VTE are detectable in 46,5% of young Hungarian VTE patients. Among them 60,7% had single and 17,8% had combined abnormalities. Recurrence rate was significantly higher in patients with more then one vs. no inherited coagulation abnormality. CVI and CU developed significantly more frequently in patients having one or even more inherited coagulation defects. The detailed detection of coagulation abnormalities is of prognostic significance. (Supported by OTKA T026428 and ETT 124/96.)
Predictors of the Development of Post-Thrombotic Syndrome after Acute Symptomatic Deep Vein Thrombosis: Two-Year Results from a Canadian Multicenter Prospective Cohort Study (The VETO Study).
Authors: Kahn Susan R. , Ducruet Thierry , Arsenault Louise , Miron Marie Jose , Roussin Andre , Desmarais Sylvie , Joyal France , Kassis Jeannine , Solymoss Susan , Ginsberg Jeffrey S. , Desjardins Louis , Johri Mira , Lamping Donna L. , Shrier Ian 
Published: April 2020

Abstract
Background and Objectives: It is not understood why some patients develop post thrombotic syndrome (PTS) after DVT while others recover without sequelae. We performed a prospective, multicenter study of long-term outcomes after DVT (the Venous Thrombosis Outcomes [VETO] Study) whose principal aim was to identify predictors of PTS.
Methods: From 2001–2002, consecutive patients with objectively diagnosed DVT were recruited at 7 hospital centres. During study visits at Baseline, 1, 4, 8, 12 and 24 months, clinical data were collected, thrombophilia testing was performed and standardized assessments for PTS (using Villalta scale) were carried out by trained personnel. Patients were classified as having developed PTS if the ipsilateral Villalta score was ≥5 on at least 2 visits or at the final follow-up visit, and severe PTS if a score of &gt;14 or a venous ulcer was documented on any one occasion. The influence of clinical, demographic, ergonomic and biological determinants on the risk of developing PTS was evaluated in bivariate and multivariate analyses.
Results: 359 patients were recruited; 49% were male, mean age was 56 years, 2/3 were outpatients and 55% had proximal DVT. The cumulative risk of PTS was 37%, of which 1 in 6 cases was severe. Patients who developed PTS, compared with those who did not, were more likely to be older (p=.005), have had previous episode(s) of DVT (p=.0003), have atherosclerosis risk factors [hypertension (p=.0002), high cholesterol (p=.02)], higher BMI (p=0.0007), longer duration of symptoms before DVT diagnosis (p=.049) and work in a job with high physical demands (p=.05), and they were less likely to have the Prothrombin gene mutation (p=0.03). Variables of interest that did not influence the risk of PTS included: sex, location of DVT (proximal vs. distal), side of DVT (left vs. right), type of DVT (cancer-related, temporary risk factors [e.g. surgery, trauma] or idiopathic), initial anticoagulation with LMWH vs. UFH, duration of warfarin, Factor V Leiden mutation or prior ipsilateral musculoskeletal condition. In adjusted multivariate analyses, BMI (odds ratio [OR] 2.1 for BMI &gt;30 vs. &lt; 30, 95% confidence interval [CI] 1.1, 4.2), previous DVT (OR 2.6, 95% CI 1.4, 4.9) and hypertension (OR 1.9, 95% CI 1.04, 3.6) were independently associated with PTS.
Conclusions: In our cohort, high BMI, previous history of DVT and hypertension were independent predictors of PTS, whereas presenting characteristics of the index DVT and its treatment did not influence the risk of developing PTS.
Regulation of Protein Kinase C by the Platelet P2Y12 ADP Receptor.
Authors: Lova Paolo , Guidetti Gianni F. , Campus Francesca , Bernardi Bruno , Balduini Cesare , Torti Mauro 
Published: April 2020

Abstract
The Gi-coupled P2Y12 receptor plays a crucial role in platelet activation induced by ADP, and is also required for the action of a number of agonists whose receptors are couple to Gq, such as thromboxane A2. Stimulation of P2Y12 leads to the inhibition of adenylyl cyclase through the Gai subunit, and to the activation of phosphatidylinositol 3-kinase (PI-3K) and Rap1b through the bg subunit. Pharmacological inhibition of P2Y12 receptor results in the prevention of platelet aggregation induced by a number of agonists, including ADP and the the thromboxane A2 analogue U46619. In this study, we report that P2Y12 receptor is absolutely necessary for the stimulation of protein kinase C (PKC) and for PKC-directed protein phosphorylation. By using 32P-labeled human platelets, as well as by immunoblotting with anti-phospho(Ser) PKC substrates antibody, we analyzed the phosphorylation of pleckstrin, the main platelet substrate for PKC. As expected, we found that ADP-induced pleckstrin phosphorylation was totally suppressed by antagonists of the Gq-coupled P2Y1 receptor, but, surprisingly, we found that it was also completely prevented upon blockade of the P2Y12 receptor by AR-C69931MX or by 2-MeSAMP. Although we failed to directly detect any production of IP3 in ADP-stimulated platelets, we observed that ADP-induced Ca2+ release from intracellular stores was not affected by P2Y12 receptor antagonists. Moreover, AR-C69931MX or 2-MeSAMP strongly impaired pleckstrin phosphorylation induced by U46619, without affecting intracellular Ca2+ mobilization. These results indicated that blockade of the P2Y12 receptor did not interfere with phospholipase C stimulation, and that the reduced activation of PKC is probably not the consequence of a reduced production of diacylglycerol. Experiments performed with specific cell permeable inhibitors demonstrated that, in ADP-treated platelets, neither inhibition of adenylyl cyclase nor activation of PI-3K downstream P2Y12 receptor stimulation was responsible for PKC regulation. Subthreshold concentrations of PMA were able to restore ADP- or U46619-induced pleckstrin phosphorylation in the presence of P2Y12 antagonists, but were unable to restore platelet aggregation. Moreover, direct inhibition of PKC by Ro31-8220 prevented ADP-induced pleckstrin phosphorylation, but aggregation occurred normally. These results indicate that although PKC-directed protein phosphorylation is targeted by the P2Y12 receptor, it is not responsible for the essential contribution of this receptor to platelet aggregation. By contrast, we found that inhibition of platelet diacylglycerol kinase by R59949 completely reverted the inhibitory effect of AR-C69931MX or 2-MeSAMP on ADP- and U46619-induced activation of PKC, and completely restored platelet aggregation. These results suggest that diacylglycerol kinase may be regulated downstream the Gi-coupled P2Y12 receptor, and may be an important new regulator of platelet aggregation.