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Adult disseminated Langerhans cell histiocytosis: incidence, racial disparities and long-term outcomes.
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Adult disseminated Langerhans cell histiocytosis: incidence, racial disparities and long-term outcomes.

Br J Haematol. 2017 Jun 27;:

Authors: Goyal G, Shah MV, Hook CC, Wolanskyj AP, Call TG, Rech KL, Go RS

PMID: 28653448 [PubMed - as supplied by publisher]




Compositional analysis gives insight into leukaemia cell lines expression profiles compared to those within patient sub-groups.
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Compositional analysis gives insight into leukaemia cell lines expression profiles compared to those within patient sub-groups.

Br J Haematol. 2017 Jun 27;:

Authors: Blayney JK, Mills KI

PMID: 28653436 [PubMed - as supplied by publisher]




Clinical heterogeneity of diffuse large B cell lymphoma following failure of front-line immunochemotherapy.
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Clinical heterogeneity of diffuse large B cell lymphoma following failure of front-line immunochemotherapy.

Br J Haematol. 2017 Jun 27;:

Authors: Farooq U, Maurer MJ, Thompson CA, Thanarajasingam G, Inwards DJ, Micallef I, Macon W, Syrbu S, Lin T, Lin Y, Ansell SM, Nowakowski GS, Habermann TM, Cerhan JR, Link BK

Abstract
This study aimed to describe the patterns of care and outcomes of diffuse large B cell lymphoma (DLBCL) after failure of front line anthracycline-based immunochemotherapy (IC). Patients with newly diagnosed lymphoma were prospectively enrolled in Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellzence. All DLBCL and primary mediastinal B-cell lymphoma (PMBL) patients treated with front-line anthracycline-based IC were followed for relapse. Patients with relapse on follow-up and subsequently retreated were included in this analysis. 1039 patients received anthracycline-based IC between 2002 and 2012, of which 244 relapsed and were subsequently retreated. Across all therapies, overall survival at 4 years (OS4) from relapse was 28% and 103 patients ultimately underwent autologous haematopoietic cell transplant (autoHCT) with OS4 from autoHCT of 51%. Patients relapsing after 12 months from initial diagnosis had OS4 of 47% but those with a transient or no response to initial therapy had OS4 of only 13%. Outcomes of relapsed or refractory DLBCL differ substantially when categorized by response to initial therapy, timing of relapse and opportunity to undergo autoHCT. The design and interpretation of uncontrolled trials should account for this heterogeneity in patients with relapsed DLBCL.

PMID: 28653407 [PubMed - as supplied by publisher]




Panobinostat plus bortezomib and dexamethasone: impact of dose intensity and administration frequency on safety in the PANORAMA 1 trial.
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Panobinostat plus bortezomib and dexamethasone: impact of dose intensity and administration frequency on safety in the PANORAMA 1 trial.

Br J Haematol. 2017 Jun 27;:

Authors: San-Miguel JF, Hungria VTM, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Guenther A, Na Nakorn T, Siritanaratkul N, Schlossman RL, Hou J, Moreau P, Lonial S, Lee JH, Einsele H, Salwender H, Sopala M, Redhu S, Paul S, Corrado C, Richardson PG

Abstract
Panobinostat in combination with bortezomib and dexamethasone demonstrated a significant and clinically meaningful progression-free survival benefit compared with placebo, bortezomib and dexamethasone in the phase 3 PANORAMA 1 (Panobinostat Oral in Multiple Myeloma 1) trial. Despite this benefit, patients in the panobinostat arm experienced higher rates of adverse events (AEs) and higher rates of discontinuation due to AEs. This PANORAMA 1 subanalysis examined AEs between 2 treatment phases of the study (TP1 and TP2), in which administration frequency of bortezomib and dexamethasone differed per protocol. The incidences of several key AEs were lower in both arms following the planned reduction of bortezomib dosing frequency in TP2. In the panobinostat arm, rates of thrombocytopenia (grade 3/4: TP1, 56·7%; TP2, 6·0%), diarrhoea (grade 3/4: TP1, 24·1%; TP2, 7·1%), and fatigue (grade 3/4: TP1, 16·3%; TP2, 1·8%) were lower in TP2 compared with TP1. Dose intensity analysis of panobinostat and bortezomib by cycle in the panobinostat arm showed reductions of both agent doses during cycles 1-4 due to dose adjustments for AEs. Exposure-adjusted analysis demonstrated a reduction in thrombocytopenia frequency in TP1 following dose adjustment. These results suggest that optimization of dosing with this regimen could improve tolerability, potentially leading to improved patient outcomes.

PMID: 28653400 [PubMed - as supplied by publisher]




Acute myeloid leukaemia genomics.
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Acute myeloid leukaemia genomics.

Br J Haematol. 2017 Jun 27;:

Authors: Medinger M, Passweg JR

Abstract
Acute myeloid leukaemia (AML) is a biologically complex, molecularly and clinically heterogeneous disease. Despite major advances in understanding the genetic landscape of AML and its impact on the pathophysiology and biology of the disease, standard treatment options have not significantly changed during the past three decades. AML is characterized by multiple somatically acquired mutations that affect genes of different functional categories. Mutations in genes encoding epigenetic modifiers, such as DNMT3A, ASXL1, TET2, IDH1, and IDH2, are commonly acquired early and are present in the founding clone. By contrast, mutations involving NPM1 or signalling molecules (e.g., FLT3, RAS gene family) are typically secondary events that occur later during leukaemogenesis. This review aims to provide an overview of advances in new prognostic markers, including targetable mutations that will probably guide the development and use of novel molecularly targeted therapies.

PMID: 28653397 [PubMed - as supplied by publisher]




Beneficial role of increased FOXP3(+) regulatory T-cells in acute myeloid leukaemia therapy response.
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Beneficial role of increased FOXP3(+) regulatory T-cells in acute myeloid leukaemia therapy response.

Br J Haematol. 2017 Jun 27;:

Authors: Menter T, Kuzmanic B, Bucher C, Medinger M, Halter J, Dirnhofer S, Tzankov A

PMID: 28653378 [PubMed - as supplied by publisher]




Decrease of externalized phosphatidylserine density on red blood cell-derived microparticles in SCA patients treated with hydroxycarbamide.
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Decrease of externalized phosphatidylserine density on red blood cell-derived microparticles in SCA patients treated with hydroxycarbamide.

Br J Haematol. 2017 Jun 27;:

Authors: Garnier Y, Ferdinand S, Connes P, Garnier M, Etienne-Julan M, Lemonne N, Romana M

PMID: 28653368 [PubMed - as supplied by publisher]




Preclinical evaluation of the BET bromodomain inhibitor BAY 1238097 for the treatment of lymphoma.
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Preclinical evaluation of the BET bromodomain inhibitor BAY 1238097 for the treatment of lymphoma.

Br J Haematol. 2017 Jun 27;:

Authors: Bernasconi E, Gaudio E, Lejeune P, Tarantelli C, Cascione L, Kwee I, Spriano F, Rinaldi A, Mensah AA, Chung E, Stathis A, Siegel S, Schmees N, Ocker M, Zucca E, Haendler B, Bertoni F

Abstract
The epigenome is often deregulated in cancer and treatment with inhibitors of bromodomain and extra-terminal proteins, the readers of epigenetic acetylation marks, represents a novel therapeutic approach. Here, we have characterized the anti-tumour activity of the novel bromodomain and extra-terminal (BET) inhibitor BAY 1238097 in preclinical lymphoma models. BAY 1238097 showed anti-proliferative activity in a large panel of lymphoma-derived cell lines, with a median 50% inhibitory concentration between 70 and 208 nmol/l. The compound showed strong anti-tumour efficacy in vivo as a single agent in two diffuse large B cell lymphoma models. Gene expression profiling showed BAY 1238097 targeted the NFKB/TLR/JAK/STAT signalling pathways, MYC and E2F1-regulated genes, cell cycle regulation and chromatin structure. The gene expression profiling signatures also highly overlapped with the signatures obtained with other BET Bromodomain inhibitors and partially overlapped with HDAC-inhibitors, mTOR inhibitors and demethylating agents. Notably, BAY 1238097 presented in vitro synergism with EZH2, mTOR and BTK inhibitors. In conclusion, the BET inhibitor BAY 1238097 presented promising anti-lymphoma preclinical activity in vitro and in vivo, mediated by the interference with biological processes driving the lymphoma cells. Our data also indicate the use of combination schemes targeting EZH2, mTOR and BTK alongside BET bromodomains.

PMID: 28653353 [PubMed - as supplied by publisher]




Fibrinogen concentration and use of fibrinogen supplementation with cryoprecipitate in patients with critical bleeding receiving massive transfusion: a bi-national cohort study.
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Fibrinogen concentration and use of fibrinogen supplementation with cryoprecipitate in patients with critical bleeding receiving massive transfusion: a bi-national cohort study.

Br J Haematol. 2017 Jun 27;:

Authors: McQuilten ZK, Bailey M, Cameron PA, Stanworth SJ, Venardos K, Wood EM, Cooper DJ

Abstract
We aimed to compare hypofibrinogenaemia prevalence in major bleeding patients across all clinical contexts, fibrinogen supplementation practice, and explore the relationship between fibrinogen concentrations and mortality. This cohort study included all adult patients from 20 hospitals across Australia and New Zealand who received massive transfusion between April 2011 and October 2015. Of 3566 patients, 2829 (79%) had fibrinogen concentration recorded, with a median first and lowest concentration of 2·0 g/l (interquartile range [IQR] 1·5-2·7) and 1·8 g/l (IQR 1·3-2·4), respectively. Liver transplant (1·7 g/l, IQR 1·2-2·1), trauma (1·8, IQR 1·3-2·5) and vascular surgery (1·9 g/l, IQR 1·4-2·5) had lower concentrations. Total median fibrinogen dose administered from all products was 7·3 g (IQR 3·3-13·0). Overall, 1732 (61%) received cryoprecipitate and 9 (<1%) fibrinogen concentrate. Time to cryoprecipitate issue in those with initial fibrinogen concentration <1 g/l was 2·5 h (IQR 1·2-4·3 h). After adjustment, initial fibrinogen concentration had a U-shaped association with in-hospital mortality [adjusted odds ratios: fibrinogen <1 g/l, 2·31 (95% confidence interval (CI) 1·48-3·60); 1-1·9 g/l, 1·29 (95% CI 0·99-1·67) and >4 g/l, 2·03 (95% CI 1·35-3·04), 2-4 g/l reference category]. The findings indicate areas for practice improvement including timely administration of cryoprecipitate, which is the most common source of concentrated fibrinogen in Australia and New Zealand.

PMID: 28653339 [PubMed - as supplied by publisher]




Quality assurance and tests of platelet function.
Related Articles

Quality assurance and tests of platelet function.

Br J Haematol. 2017 Jun 27;:

Authors: Jennings I, Perry D, Watson H, Alikhan R, Laffan M, Gomez K, Kitchen S, Walker I, Haemostasis and Thrombosis Task Force of the British Society for Haematology & UK NEQAS for Blood Coagulation

PMID: 28653330 [PubMed - as supplied by publisher]




Increased fracture risk in plasma cell dyscrasias is associated with poorer overall survival.
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Increased fracture risk in plasma cell dyscrasias is associated with poorer overall survival.

Br J Haematol. 2017 Jun 27;:

Authors: McIlroy G, Mytton J, Evison F, Yadav P, Drayson MT, Cook M, Pratt G, Cockwell P, Pinney JH

Abstract
Pathological fractures are a common complication of plasma cell dyscrasias (PCD) and are associated with significant morbidity. Routine use of bisphosphonates over the past decade has aimed to reduce the risk of fractures in patients with multiple myeloma, but despite this, fractures continue to represent a significant burden of disease. In this study we report the fracture rate of hospital in-patients with PCD in England. Data from the national registry Hospital Episode Statistics between 2001 and 2015 were used to determine fracture rate and its effect on overall survival. Fracture rates were 17·8 times higher than the general population in the first year after admission with PCD, and remained elevated for up to 10 years after first admission. The increased fracture risk preceded the first admission with PCD and, conversely, the incidence of PCD increased after admission with one or more fractures. Overall survival is improving with PCD, however poorer survival is found in patients with a preceding fracture (Hazard ratio 1·20). Despite widespread bisphosphonate use, fractures remain common in PCD, and are associated with poorer outcomes.

PMID: 28653323 [PubMed - as supplied by publisher]




Clinical and treatment-related features determining the risk of late relapse in patients with diffuse large B-cell lymphoma.
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Clinical and treatment-related features determining the risk of late relapse in patients with diffuse large B-cell lymphoma.

Br J Haematol. 2017 Jun 27;:

Authors: Modvig L, Vase M, d'Amore F

Abstract
It is still unclear whether there are clinically exploitable differences in the biology and behaviour of early versus late relapses in diffuse large B-cell lymphoma (DLBCL). The present study aimed to analyse a large population-based DLBCL cohort in order to identify (i) the frequency of late relapses (LR), (ii) parameters influencing the risk of LR, and (iii) the impact of introducing rituximab on the occurrence of LR. The data of 7247 DLBCL patients was obtained from the Danish Lymphoma Group Registry. Patients with LR had a lower International Prognostic Index and better performance score than early relapse (ER) patients. The use of radiotherapy lowered only the rate of ER while the use of rituximab yielded a lower occurrence of both ER and LR (P < 0·0001 and P < 0·0001, respectively), possibly suggesting a longer-lasting biological effect. Additionally, we found a female overrepresentation among LR patients that had received a rituximab-containing first line treatment. It was found that patients with LR had a significantly better 5-year overall survival compared to ER patients. In conclusion, LR was more frequently associated with low-risk features than ER. Furthermore, we found that the use of modern immunochemotherapy regimens in DLBCL lowers the risk of both ER and LR.

PMID: 28653321 [PubMed - as supplied by publisher]