bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Thrombin Inhibitor, but Not a Factor Xa Inhibitor, DU-176b, Aggravates Tissue Factor-Induced Hypercoagulation in Rats.
Authors: Morishima Yoshiyuki , Fukuda Toshio , Tsuji Naoki , Honda Yuko , Matsumoto Chikako , Furugohri Taketoshi , Shibano Toshiro 
Published: October 2019

Abstract
There is rising concern about recurrent thrombotic events after cessation of anticoagulant therapies. Withdrawal of heparins and a direct thrombin inhibitor is reported to be associated with evidence of rebound coagulation phenomenon in patients with coronary artery diseases (Ref 1). Previously we have shown that low-dose administration of a direct thrombin inhibitor, melagatran, worsens consumption of platelet induced by tissue factor (TF) injection (Ref 2).
Objective: To determine whether cessation of melagatran, but not a factor Xa (FXa) inhibitor, DU-176b, aggravates TF-induced hypercoagulation in a rat in vivo model.
Methods: Under halothane anesthesia, melagatran (2 mg/kg, i.v. bolus) and DU-176b (0.3 mg/kg, i.v. bolus) were injected into the jugular vein of male Wistar rats. Five min, 2, 4, 8, and 16 hr after dosing, hypercoagulation was induced by injection of 2.8 U/kg TF into the femoral vein of rats anesthetized with thiopental. Blood samples were collected 10 min after TF injection. Platelet numbers and TAT concentrations were measured.
Results: Both melagatran and DU-176b inhibited platelet consumption and thrombin-antithrombin complex (TAT) generation when hypercoagulation was induced 5 min after the drug administration. This indicated that these compounds effectively inhibited hypercoagulation at this time point. Melagatran, however, 2 and 4 hr after dosing enhanced platelet consumption and TAT generation, indicating that the thrombin inhibitor aggravated hypercoagulation at these time points. Much later (8 and 16 hr), the effects of melagatran towards inhibition or enhancement disappeared. In contrast, DU-176b did not show any exacerbation of TF-induced hypercoagulation.
Conclusion: Cessation of a direct thrombin inhibitor, melagatran, is associated with aggravation of coagulation status. This phenomenon may be implicated in rebound coagulation activation observed in clinical settings. On the other hand, the FXa inhibitor, DU-176b, may be beneficial because of a low risk of recurrent activation of coagulation pathway after cessation.
Prasugrel (CS-747, LY640315) Hydrochloride, a Novel Thienopyridine Prodrug, Shows Potent Antiplatelet and Antithrombotic Effects with Rapid Onset of Action in Rats.
Authors: Niitsu Yoichi , Ogawa Taketoshi , Sugidachi Atsuhiro , Jakubowski Joseph A. , Yokouchi Yuki , Kakusaka Mayumi , Hasegawa Michihiro , Asai Fumitoshi 
Published: October 2019

Abstract
The thienopyridine antiplatelet prodrug clopidogrel bisulfate (C) is widely used for atherothrombotic diseases. However, several reports have described a limitation of C, namely, poor platelet inhibition in many patients following oral dosing. Prasugrel (hydrochloride), currently under investigation in a Phase 3 trial in acute coronary syndrome patients undergoing percutaneous coronary intervention, is a novel thienopyridine antiplatelet prodrug. In recent clinical studies, prasugrel has shown more consistent platelet inhibition than C. To date, several preclinical studies have demonstrated that the prasugrel base formulation has more potent antiplatelet and antithrombotic effects than C. The effects of prasugrel hydrochloride (P), which has a higher solubility than the base formulation, have not been reported. The present studies examined the effects of P on platelet aggregation, arterial thrombosis, and bleeding time in rats. Single oral administration of P (0.3 to 3 mg/kg) resulted in inhibition of platelet aggregation (IPA) induced by ADP in a dose- and time-related manner with an ED50 value of 1.1 mg/kg at 4 hr postdose. After dosing of 3 and 10 mg/kg P, statistically significant IPA was observed at 30 and 15 min, and the time required to achieve 50% IPA was approximately 50 and 23 min, respectively (Figure). These results indicate that P has potent antiplatelet effects with an extremely fast onset of action. Multiple P dosing also resulted in potent IPA, with an ED50 value of 0.45 mg/kg/day (p.o.) at 4 hr after the last dose. Our previous report indicated an ED50 value of C at 4 hr after single oral dosing of 16 mg/kg (Br. J. Pharmacol. 129, 1439, 2000), demonstrating about 10-times greater potency of P compared to C. Potent dose-related antithrombotic effects of P were further confirmed in an arterial thrombosis model in rats. P (0.1–1 mg/kg, p.o.) inhibited thrombus formation in the arterial thrombosis induced by extravascular application of FeCl3 solution. All these results taken together indicate that prasugrel hydrochloride is a novel, potent and fast acting thienopyridine prodrug, potentially providing superior efficacy in the treatment of atherothrombotic disorders.
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Contribution of Nucleic Acid Testing of Plasma Source Material to the Viral Safety of Plasma Derived Coagulation Factors: The French Experience.
Authors: Visse Catherine , Flan Benoit 
Published: October 2019

Abstract
Viral testing of donations and plasma pools is one of the important elements that guarantee the safety of plasma-derived coagulation factors towards the risk of transmitting pathogenic agents. In the last decade, virus testing has benefited from developments in Nucleic Acid Testing (NAT), which has permitted its implementation initially for the testing of plasma pools and more recently at the donation level. Validated NAT techniques significantly increase the safety margin of plasma-derived products by reducing the initial viral load, which could challenge the efficacy of viral inactivation or elimination during the manufacturing processes. NAT for major blood borne viruses such as HIV and HCV allows the detection of the virus during the window period where the donor may escape from serological detection and the viral load can be very high. Implementation of HCV-NAT on plasma pools in France, has allowed detection of 7 HCV RNA positive/anti-HCV negative donations amongst 8.6 million donations tested (period 1997 – 2001) corresponding to an incidence rate of 1/1 230 000 donations, correlating with the extremely low residual HCV transfusion risk in France. NAT has also been voluntarily applied to increase the safety of coagulation factors with regards to non-enveloped viruses, mostly Parvovirus B19 (B19V) and hepatitis A virus (HAV). These viruses have been transmitted through inactivated coagulation factors because they are more resistant to viral inactivation treatments (e.g. Solvent/Detergent treatment) than enveloped viruses. Very high viremia are observed in B19V infection and testing B19 DNA in manufacturing plasma pools with a threshold concentration of 104 IU/ml allowed a dramatic reduction in the initial viral load (reduction factor ~ 6 – 7 log10). After nearly 10-years experience in France, which is the longest experience reported, the mean incidence rate is 1 in 7 710 donations, with epidemics detected in 1997 and 2005. Annual incidence profiles confirm a seasonal evolution of this virus with an increased incidence in the spring period. The contribution of B19 NAT to the increased safety of coagulation factors is supported by pharmacovigilance data in France, with no reports of B19V transmission associated with a coagulation factor since NATs implementation. NAT represents a significant breakthrough in the viral testing of plasma for fractionation. Automated systems in place can readily be adapted to emerging pathogens as shown, in Northern American countries, with the rapid implementation of West Nile Virus PCR testing in the transfusion setting. NAT represents a state of the art development in the manufacture of increasingly safe plasma-derived products.
Histology of Lymphomas with t(3;14)(q27;q32) Correlates with the Molecular Anatomy of the Translocation.
Authors: Ruminy Philippe , Jardin Fabrice , Picquenot Jean-Michel , Gaulard Philippe , Parmentier Françoise , Buchonnet Gérard , Maisonneuve Claire , Tilly Hervé , Bastard Christian 
Published: October 2019

Abstract
The t(3;14)(q27;q32) is the most common translocation involving BCL6 in non Hodgkin B-cell lymphoma. Although this translocation has been predominantly associated with diffuse large B-cell lymphoma (DLBCL), recent studies have shown that it can also be found in follicular lymphomas (FL), where it is often associated with a large cell component. To further investigate the relationship that might exist between this translocation and the phenotype of the tumor, we studied 34 B-cell lymphomas with t(3;14)(q27;q32) and diffuse or follicular growth patterns. As the t(3;14)(q27;q32), involving telomeric ends of both chromosomes 3 and 14, is often difficult to detect by conventional cytogenetic, it should be emphasised that only t(3;14) positive FL or DLBCL where the translocation could be validated either by molecular technics (cloning of the breakpoint, amplification of specific IGH-BCL6 fusion transcripts or fluorescence in situ hybridization) were retained in this study. Noteworthy, none of the samples were found to have a t(14;18), indicating that the two most frequent translocations in B-cell NHL, both seen as early transforming events, are usually exclusive. This observation is in agreement with the hypothesis that BCL2 and BCL6 deregulations probably constitute two different lymphomagenesis pathways. Our data also indicate that most t(3;14) positive DLBCL share a CD10−/BCL6+/MUM1+ phenotype (10/16, 62%) and can be classified in the non-germinal centre subgroup (12/16, 75%)%), while a majority of t(3;14) positive FL are CD10− and BCL6+ (10/12, 83%). Moreover, we identified the IGH switch region (S) involved in the translocation for 32 cases, either by cloning the genomic breakpoint (27 cases), and/or by amplifying the IGH-BCL6 fusion transcripts expressed by the tumors (26 cases). For 17/19 (89%) DLBCL or FL with DLBCL, the translocation involved the Sμ, while for 9/13 (70%) FL with no diffuse areas of proliferation the t(3;14) involved a Sγ. These results indicate that the histology of the tumor and the structure of the translocated allele are correlated (p=0.0016), suggesting that the substituted regulatory regions that comes to deregulate BCL6 after a t(3;14) may affect the presentation of the disease.
Conditional Survival of Patients with Diffuse Large B-Cell Lymphoma.
Authors: Moller Michael B. , Pedersen Niels T. , Christensen Bjarne E. 
Published: October 2019

Abstract
Purpose: Prognosis of lymphoma patients is usually estimated at the time of diagnosis, and the estimates are guided by the International Prognostic Index (IPI). However, survival rates calculated at the time of diagnosis may not be predictive of outcome for patients who have survived 1 or more years. For these patients conditional survival is more informative as only those patients who have already survived a period of time after treatment are considered. Conditional survival data have not been reported for lymphoma patients and the impact of the IPI on conditional survival is not known.
Patients and Methods: Conditional survival was estimated for 1,209 patients with diffuse large B-cell lymphoma from the population-based LYFO-registry of the Danish Lymphoma Group. The patients were diagnosed between 1983 and 1998 with a median follow-up time of 7.8 years, and all patients were treated with curative intent. The Kaplan-Meier method was used to estimate conditional survival at 0–5 years after diagnosis.
Results: The probability of surviving 5 years increased with each year survived for the first 3 years after diagnosis (from 43% to 70%) after which the increase was minimal (Figure 1). The median survival increased from 38 months for all patients to between 108 and 120 months conditioned on survival for at least 3 to 5 years. The distribution of patients in the IPI risk groups changed significantly over time. However this effect was only seen in the first 5 years. At diagnosis, 28% of the patients were allocated to the high-intermediate and high-risk groups, but only 11% of patients who survived 5 years were from these risk groups (P < .0001). Risk group allocation did not change the following 5 years (P = .7747). At the time of diagnosis overall survival differed greatly between the IPI risk groups (P < .0001; figure 2). However, 5 years after diagnosis the rates were similar (P = .0586). Furthermore, the prognostic impact of the individual clinical variables of the IPI (age, stage, performance score, LDH, and extranodal disease) was also significant at diagnosis, but 2 years after diagnosis only age had prognostic impact. Multivariate analysis (including the IPI and the individual IPI variables) of patients who survived ≥3 years identified only age as a prognostic factor (relative risk 4.1; P < .001).
Conclusion: For patients with diffuse large B-cell lymphoma who have survived more than 1 year after diagnosis, the conditional survival probability provides more accurate prognostic information than the conventional survival rate estimated from the time of diagnosis. Furthermore, age is the most important factor for long-term survival, whereas the remaining IPI factors are not informative.
Figure Figure Figure Figure
Lack of BIC and microRNA miR-155 Expression in Primary Cases of Burkitt Lymphoma.
Authors: Kluiver Joost , Haralambieva Eugenia , de Jong Debora , Blokzijl Tjasso , Jacobs Susan , Kroesen Bart-Jan , Poppema Sibrand , van den Berg Anke 
Published: October 2019

Abstract
We previously demonstrated a high expression of primary-microRNA BIC (pri-miRNA-155) in Hodgkin lymphoma (HL) and lack of expression in most non-Hodgkin lymphoma subtypes including some Burkitt lymphoma (BL) cases. Recently, a high expression of BIC was reported in BL in comparison to pediatric leukemia and normal peripheral blood samples. In this study we extended our series of BL cases and cell lines for BIC expression by RNA in-situ hybridization (ISH) and quantitative (q)RT-PCR. Both BIC RNA-ISH and qRT-PCR revealed no or only low levels of BIC in 25 BL tissues, including 7 Epstein-Barr virus (EBV) positive cases, compared to HL and normal controls. In agreement with these findings, Northern blotting revealed absence of miR-155 in BL tissues. EBV negative and EBV latency type I BL cell lines also showed very low BIC and miR-155 expression levels as compared to HL cell lines. Higher levels of BIC and miR-155 were detected in in vitro transformed lymphoblastoid EBV latency type III BL cell lines. An association of latency type III infection and induction of BIC was supported by consistent expression of BIC in 11 and miR-155 in 2 posttransplantation lymphoproliferative disorder (PTLD) cases. In summary, we demonstrated that expression of BIC and miR-155 is not a common finding in BL. Expression of BIC and miR-155 in 3 latency type III EBV positive BL cell lines and in all primary PTLD cases suggests a possible role for EBV latency type III specific proteins in the induction of BIC expression.
CD19-Negative Diffuse Large B-Cell Lymphoma Shows High Serum LDH Level and Poor Prognosis.
Authors: Kimura Miho , Yamaguchi Motoko , Ueno Satoshi , Ogawa Shoko , Miyazaki Kana , Oka Kouji , Kobayashi Tohru , Shiku Hiroshi 
Published: October 2019

Abstract
CD19 is one of the most representative B-cell markers, and is widely used in diagnostic immunophenotyping in diffuse large B-cell lymphoma (DLBCL). However, it is known that the frequency of CD19 expression in DLBCL is less than that of CD20, and the clinical significance of CD19 expression has not yet been thoroughly examined. To clarify the clinical behavior of CD19-negative (CD19−) DLBCL, we have compared the clinical features, immunophenotype, and prognosis in relation to CD19 expression. The diagnosis of DLBCL was made according to the WHO Classification. We examined CD19 expression by means of immunohistochemistry using frozen sections with a monoclonal antibody, Leu12 (Becton Dickinson). Between 1987 and 2002, 227 cases of de novo DLBCL were examined the expression of CD19 in our laboratory. Anthracycline-containing chemotherapies were selected as the first-line treatment in 192 cases (85%). None was treated with rituximab. CD19 was expressed in 205 cases (90%), and 226 cases (99%) were positive for CD20. In 22 cases of CD19-negative (CD19−) DLBCL, the median age was 63 (39–79), and the male/female ratio was 11/11. According to CD19 expression, our DLBCL cases showed the following clinical features: male/female (CD19+ DLBCL 111/94, CD19− DLBCL 11/11: NS), age>60 (70%, 55%: NS), PS>1 (20%, 36%: P=0.07), sLDH>1xN (44%, 73%: P=0.01), extranodal involvement>1 site (12%, 18%: NS), stage III/IV (41%, 54%: NS), B symptom present (29%, 45%: NS). CD19− DLBCL expressed BCL2 protein less frequently than CD19+ DLBCL (P=0.03). The expression of CD5, CD10, CD21, BCL6, and MUM1 did not show a significant difference between CD19+ DLBCL and CD19− DLBCL. CD19− DLBCL showed significantly worse survival than CD19+ DLBCL (P=0.04, log-rank test). These findings suggest that the loss of CD19 expression in DLBCL is associated with high serum LDH level and poor prognosis. Simultaneous examination of CD19 and CD20 in diagnosis of DLBCL is recommended.
Overall survival for patients with CD19+ DLBCL and with CD19− DLBCL. Overall survival for patients with CD19+ DLBCL and with CD19− DLBCL.
A Mid-Treatment FDG-Positron Emission Tomography (PET) Scan Is Highly Predictive of Subsequent Treatment Failure in Patients with Diffuse Large B-Cell Lymphoma (DLBCL).
Authors: Ng Ashley P. , Lee Michael , Hogg Annette , Seymour John F. , Janusewicz Henry , Prince Miles , MacManus Michael , Hicks Rod , Wirth Andrew 
Published: October 2019

Abstract
AIMS Computerised Tomography (CT) scanning is the primary modality for assessment of therapeutic response in DLBCL. We evaluated whether functional imaging utilising FDG-PET may provide additional prognostic information in response assessment prior to completion of chemotherapy for patients with DLBCL.
METHODS We performed a retrospective, single-centre study of patients with DLBCL who received anthracycline-based chemotherapy +/− radiotherapy (RT) and had PET prior to completion of therapy.
RESULTS From 1996–2004 there were 45 eligible patients. Median age was 59 years (range 26–82) with disease stage I–II (n=25) or III–IV (n=20). Median IPI was 2[IPI 0–2(n=27), IPI 3–4(n=13)] in 40 evaluable patients. Therapy included full-course CHOP/CHOP-like therapy (n=26); HyperCVAD (n=6) and limited (3–4 cycles) CHOP/CHOP-like chemotherapy with RT (n=13). Rituximab was used concurrently in 18 patients. Planned RT was administered in 23 patients. 13 (29%) patients were PET positive after a median of 3 chemotherapy cycles (range 1–5). Of these, 7 (54%) progressed a median of 7.2 months following completion of therapy. Of the 6 progression-free, 4 demonstrated residual low-grade activity at sites of prior bone involvement (median follow-up 50.8 months), while 2 patients (stage I and IV disease) had limited follow-up (<8 months). Of 32 patients who were PET-negative, only 3 have progressed (median 7.7 months follow-up); 2 with stage IV (IPI 1 and 2 respectively) and 1 with stage I disease. Overall the Positive predictive value (PPV) of a positive-interim PET was 58.3% [Hazard Ratio of 6.67 (95% C.I. 2.6 – 46.3)] and Negative PV(NPV) was 90.9% (see figure 1). Excluding patients with Stage IE bone lymphoma (see Figure 2), the PPV of positive-interim PET was 88%(77–98%) and NPV was 91%(82–100%). The median number of chemotherapy cycles after which PET was performed was equivalent according to interim PET status (3 cycles) as was median baseline IPI [IPI 2(PET-positive), IPI 1.5(PET-negative); p=0.17].
CONCLUSIONS Patients with DLBCL receiving chemotherapy who have persisting PET-positivity during their therapy have a greatly increased risk of treatment failure and should be considered for treatment intensification. Bone lymphoma may represent a distinct entity with a good prognosis despite some minor persisting PET-positivity prior to completion of therapy.
Patients in remission Patients in remission Patients in Remission excluding Stage IE Bone DLBCL Patients in Remission excluding Stage IE Bone DLBCL
Allogeneic Stem Cell Transplantation with Peripheral Blood Stem Cells Mobilized by Pegylated-G-CSF.
Authors: Hill Geoff , Morris Edward S. , Fuery Maddona , Hutchins Cheryl , Butler Jason , Grigg Andrew , Roberts Andrew , Bradstock Ken , Szer Jeffrey , Kennedy Glen , Morton James , Durrant Simon 
Published: October 2019

Abstract
The mobilization of stem cells with pegylated-G-CSF (peg-G-CSF) modulates regulatory T cell and NKT cell function, separating graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effects in animal models. We have initiated a phase I/II study to analyse the feasibility of mobilizing stem cells from sibling donors with peg-G-CSF and their ability to restore hematopoiesis in HLA matched transplant recipients who have received myeloablative conditioning. Results were compared to a cohort of donors mobilized with standard G-CSF at 10ug/kg/day (n=19). The administration of 6mg of peg-G-CSF (n=6) resulted in suboptimal stem cell mobilization with a peak peripheral blood CD34+ count of 29 ± 4/uL. Apheresis 4 days after peg-G-CSF administration yielded 2.7 ± 0.3 x106 CD34+ cells/kg recipient ideal body weight and all patients required a second collection on day 5 to yield a total of 4.0 ± 0.5 x106 CD34+ cells/kg recipient weight. Following escalation of the dose to 12mg (n=9), the peak CD34+ count was 109 ± 13/uL and all donors collected sufficient stem cells for transplantation in a single apheresis (9.8 ± 1.7 x106 CD34+ cells/kg recipient weight). The 6mg dose of peg-G-CSF was significantly inferior to standard G-CSF for stem cell mobilization (P<0.01) while the 12mg dose was at least equivalent (P=0.07).
Bone pain was similar between the 6mg and 12mg cohorts and to that seen with standard G-CSF. However, in addition to the expected rises in serum ALP and LDH, transient rises in hepatic transaminases were noted 5 to 12 days after peg-G-CSF administration in 7 of 9 donors receiving the 12mg dose. One donor developed NCI grade 3 hepatic toxicity and splenomegaly. After allogeneic transplantation of peg-G-CSF mobilized grafts (Cy/TBI conditioning in 13 of 14 recipients), median neutrophil and platelet engraftment occurred on days 18 and 14 respectively and was identical to that seen with grafts mobilized by standard G-CSF. With a median follow up of 165 days (range 55–532), the incidence of grade II-IV and grade III/IV acute GVHD is 50% and 21% respectively. No patients have relapsed to date and overall survival is 86%. The mobilization of stem cells with peg-G-CSF in normal donors is feasible and 12mg appears the optimal dose. Further data are required to more closely analyse the effect of peg-G-CSF on donor liver function and the ability of stem cell grafts to separate GVHD and GVL effects.
Figure Figure