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Diagnostic and prognostic roles of circulating exosomal microRNAs in acquired aplastic anemia and myelodysplastic syndromes.
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Diagnostic and prognostic roles of circulating exosomal microRNAs in acquired aplastic anemia and myelodysplastic syndromes.

Haematologica. 2018 Apr 19;:

Authors: Giudice V, Banaszak LG, Gutierrez-Rodrigues F, Kajigaya S, Panjwani R, Fernandez Ibanez MDP, Rios O, Bleck CK, Stempinski ES, Quinones Raffo D, Townsley DM, Young NS

Abstract
Exosomal microRNAs modulate cancer cell metabolism and the immune response. Specific exosomal microRNAs have been reported to be reliable biomarkers of several solid and hematologic malignancies. We examined the possible diagnostic and prognostic values of exosomal microRNAs in two human bone marrow failure diseases, aplastic anemia and myelodysplastic syndromes. After screening of 372 microRNAs in a discovery set (n=42) of plasma exosome samples, we constructed a custom microRNA PCR plate, including 42 microRNAs, for validation in a larger cohort (n=99), and we identified 25 differentially expressed exosomal microRNAs uniquely or frequently present in aplastic anemia and/or myelodysplastic syndromes. These microRNAs could be related to intracellular functions, such as metabolism, cell survival, and proliferation. Clinical parameters and progression-free survival were correlated to microRNA expression levels in myelodysplastic syndromes and aplastic anemia patients before and after 6 months of immunosuppressive therapy. One microRNA, mir-126-5p, was negatively correlated with a response to therapy in aplastic anemia: patients with higher relative expression of miR-126-5p at diagnosis had the shortest progression-free survival compared to those with lower or normal levels. Our findings support the use of exosomal microRNAs in the differential diagnosis of bone marrow failure syndromes and their measurement may be useful in determining prognosis in those patients.

PMID: 29674506 [PubMed - as supplied by publisher]




C-reactive protein and risk of venous thromboembolism: Results from a population-based case-crossover study.
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C-reactive protein and risk of venous thromboembolism: Results from a population-based case-crossover study.

Haematologica. 2018 Apr 19;:

Authors: Grimnes G, Isaksen T, Tichelaar YIGV, Brox J, Brækkan SK, Hansen JB

Abstract
Long-term, low-grade inflammation does not seem to be a risk factor for venous thromboembolism. The impact of acute inflammation, regardless of cause, on risk of venous thromboembolism is scarcely studied. We aimed to investigate the impact of acute inflammation, assessed by C-reactive protein, on short-term risk of venous thromboembolism. We conducted a case-crossover study of patients with venous thromboembolism (n=707) recruited from a general population. Information on triggers and C-reactive protein levels were retrieved from hospital records during the 90 days before the event (hazard period) and in four preceding 90 day control periods. Conditional logistic regression was used to obtain β coefficients for change in natural log (ln) transformed C-reactive protein from control to hazard periods and to determine corresponding odds ratios for venous thromboembolism. Median C-reactive protein was 107 mg/L in the hazard period, and ranged from 7 mg/L to 16 mg/L in the control periods. The level of C-reactive protein was 58% (95% CI 39-77%) higher in the hazard period than in the control periods. A one-unit increase in ln-C-reactive protein was associated with increased risk of venous thromboembolism (OR 1.79, 95% CI 1.48-2.16). The risk estimates were only slightly attenuated after adjustment for immobilization and infection. In stratified analyses, ln-C-reactive protein was associated with increased risk of venous thromboembolism in cases with (OR 1.55, 95% CI 1.01-2.38) and without infection (OR 1.77, 95% CI 1.22-2.57). In conclusion, we found that acute inflammation, assessed by C-reactive protein, was a trigger for venous thromboembolism.

PMID: 29674505 [PubMed - as supplied by publisher]




Efficacy of bendamustine and rituximab as first salvage treatment in chronic lymphocytic leukemia and indirect comparison with ibrutinib: a GIMEMA, ERIC and UK CLL FORUM study.
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Efficacy of bendamustine and rituximab as first salvage treatment in chronic lymphocytic leukemia and indirect comparison with ibrutinib: a GIMEMA, ERIC and UK CLL FORUM study.

Haematologica. 2018 Apr 19;:

Authors: Cuneo A, Follows G, Rigolin GM, Piciocchi A, Tedeschi A, Trentin L, Medina Perez A, Coscia M, Laurenti L, Musuraca G, Farina L, Rivas Delgado A, Orlandi EM, Galieni P, Mauro FR, Visco C, Amendola A, Billio A, Marasca R, Chiarenza A, Meneghini V, Ilariucci F, Marchetti M, Molica S, Re F, Gaidano G, Gonzalez M, Forconi F, Ciolli S, Cortelezzi A, Montillo M, Smolej L, Schuh A, Eyre TA, Kennedy B, Bowles KM, Vignetti M, de la Serna J, Moreno C, Foà R, Ghia P

Abstract
We performed an observational study on the efficacy of bendamustine and rituximab as first salvage regimen in chronic lymphocytic leukemia. In an intention-to-treat analysis including 237 patients, the median progression free survival was 25 months. The presence of del(17p), unmutated IGHV and advanced stage were associated with a shorter progression free survival at multivariate analysis. The median time-to-next treatment was 31.3 months. Front-line treatment with a chemoimmunotherapy regimen was the only predictive factor for a shorter time to next treatment at multivariate analysis. The median overall survival was 74.5 months. Advanced Binet stage (i.e. III-IV or C) and resistant disease were the only parameters significantly associated with a shorter OS. Grade 3-5 infections were recorded in 6.3% of patients. A matched-adjusted indirect comparison with ibrutinib given second-line within named patient programs in the United Kingdom and in Italy was carried out with overall survival as objective endpoint. When restricting the analysis to patients with intact 17p who had received chemoimmunotherapy in first line, the overall survival did not differ between patients treated with ibrutinib (63% alive at 36 months) and patients treated with BR (74.4% alive at 36 months). BR is an efficacious first salvage regimen in chronic lymphocytic leukemia in a real-life population, including the elderly and unfit patients. BR and ibrutinib may be equally effective in terms of overall survival when used as first salvage treatment in patients without 17p deletion. ClinicalTrials.gov identifier: NCT02491398.

PMID: 29674504 [PubMed - as supplied by publisher]




Dexamethasone promotes durable factor VIII -specific tolerance in hemophilia A mice via thymic mechanisms.
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Dexamethasone promotes durable factor VIII -specific tolerance in hemophilia A mice via thymic mechanisms.

Haematologica. 2018 Apr 19;:

Authors: Georgescu MT, Moorehead PC, van Velzen AS, Nesbitt K, Reipert BM, Steinitz KN, Schuster M, Hough C, Lillicrap D

Abstract
The development of inhibitory antibodies to factor VIII is the most serious complication of replacement therapy in hemophilia A. Activation of the innate immune system during exposure to this protein contributes to inhibitor development. However, avoidance of factor VIII exposure during innate immune system activation by external stimuli (e.g. vaccines) has not been consistently shown to prevent inhibitors. We hypothesized that dexamethasone, a drug with potent anti-inflammatory effects, could prevent inhibitors by promoting immunologic tolerance to factor VIII in hemophilia A mice. Transient dexamethasone treatment during initial factor VIII exposure reduced the incidence of anti-factor VIII immunoglobulin G in both a conventional hemophilia A mouse model (E16KO, 77% vs. 100%, p=0.048) and a hemophilia A mouse model with a humanized major histocompatibility complex type II transgene (E17KO/hMHC, 6% vs. 33%, p=0.0048). More importantly, among E17KO/hMHC mice that did not develop anti-factor VIII immunoglobulin G after initial exposure, dexamethasone-treated mice were less likely to develop a response after re-exposure 6 (7% vs. 52%, p=0.005) and 16 weeks later (7% vs. 50%, p=0.097). Similar results were obtained even when factor VIII re-exposure occurred in the context of lipopolysaccharide (30% vs. 100%, p=0.069). The ability of these mice to develop immunoglobulin G to human von Willebrand factor, a structurally unrelated antigen, remained unaffected by treatment. Transient dexamethasone administration therefore promotes antigen-specific immunologic tolerance to factor VIII. This effect is associated with an increase in the percentage of thymic regulatory T cells (12.06% vs. 4.73%, p<0.001) and changes in the thymic mRNA transcription profile.

PMID: 29674503 [PubMed - as supplied by publisher]




Dissecting the pathophysiology of immune thrombotic thrombocytopenic purpura: interplay between genes and environmental triggers.
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Dissecting the pathophysiology of immune thrombotic thrombocytopenic purpura: interplay between genes and environmental triggers.

Haematologica. 2018 Apr 19;:

Authors: Hrdinová J, D'Angelo S, Graça NAG, Ercig B, Vanhoorelbeke K, Veyradier A, Voorberg J, Coppo P

Abstract
Although outstanding progress has been made in comprehending the pathophysiology of thrombotic thrombocytopenic purpura, our understanding of the immunopathogenesis of the disease is only in its earlier stage. Anti-ADAMTS13 auto-antibodies were shown to block proteolysis of von Willebrand factor and/or induce ADAMTS13 clearance from the circulation. However, which immune cells are involved in the production of anti-ADAMTS13 autoantibodies and hence account for the remarkable efficacy of the B-cell depleting agents in this disease, remain to be identified. The mechanisms leading to the loss of tolerance of the immune system towards ADAMTS13 involve the predisposing genetic factors of the human leukocyte antigen class II locus DRB1*11 and DQB1*03 alleles as well as the protective allele DRB1*04, and modifying factors such as ethnicity, sex and obesity. In the forthcoming years, studies will have to identify why these identified genetic risk factors are also frequently found in the healthy population although the incidence of immune-mediated thrombotic thrombocytopenic purpura is extremely low. Moreover, the development of recombinant ADAMTS13 opens a new therapeutic era in the field. Interactions of recombinant ADAMTS13 with the immune system of immune-mediated thrombotic thrombocytopenic purpura patients will require intensive investigation, especially for its potential immunogenicity. Better understanding of immune-mediated thrombotic thrombocytopenic purpura immunopathogenesis should therefore provide a basis for the development of novel therapeutic approaches to restore immune tolerance towards ADAMTS13 and thereby better prevent refractoriness and relapses in patients with immune-mediated thrombotic thrombocytopenic purpura. In this review, we address these aspects and the accompanying challenges in the field.

PMID: 29674502 [PubMed - as supplied by publisher]




Evaluation of serum markers for improved detection of autologous blood transfusions.
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Evaluation of serum markers for improved detection of autologous blood transfusions.

Haematologica. 2018 Apr 19;:

Authors: Cox HD, Miller GD, Lai A, Cushman D, Ganz T, Eichner D

PMID: 29674501 [PubMed - as supplied by publisher]




Novel GPR34 and CCR6 mutation and distinct genetic profiles in MALT lymphomas of different sites.
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Novel GPR34 and CCR6 mutation and distinct genetic profiles in MALT lymphomas of different sites.

Haematologica. 2018 Apr 19;:

Authors: Moody S, Thompson JS, Chuang SS, Liu H, Raderer M, Vassiliou G, Wlodarska I, Wu F, Cogliatti S, Robson A, Ashton-Key M, Bi Y, Goodlad J, Du MQ

Abstract
MALT lymphoma originates from a background of diverse chronic inflammatory disorders at various anatomic sites. The genetics underlying its development, particularly in those associated with autoimmune disorders, is poorly characterised. By whole exome sequencing of 21 cases of MALT lymphomas of the salivary gland and thyroid, we have identified recurrent somatic mutations in 2 G-protein coupled receptors (GPR34 and CCR6) not previously reported in human malignancies, 3 genes (PIK3CD, TET2, TNFRSF14) not previously implicated in MALT lymphoma, and a further 2 genes (TBL1XR1, NOTCH1) recently described in MALT lymphoma. The majority of mutations in GPR34 and CCR6 were nonsense and frameshift changes clustered in the C-terminal cytoplasmic tail, and would result in truncated proteins that lack the phosphorylation motif important for β-arrestin mediated receptor desensitization and internalisation. Screening of these newly identified mutations, together with previously identified genetic changes, identified distinct mutation profiles in MALT lymphoma of various sites, with those of salivary gland characterised by frequent TBL1XR1 and GPR34 mutations, thyroid by frequent TET2, TNFRSF14 and PIK3CD mutations, and ocular adnexa by frequent TNFAIP3 mutation. Interestingly, in MALT lymphoma of the salivary gland, there was a significant positive association between TBL1XR1 mutation and GPR34 mutation/translocation (P=0.0002). In those of ocular adnexa, TBL1XR1 mutation was mutually exclusive from TNFAIP3 mutation (P=0.049), but significantly associated with IGHV3-23 usage (P=0.03) and PIK3CD mutation (P=0.009). These findings unravel novel insights into the molecular mechanisms of MALT lymphoma and provide further evidence for potential oncogenic cooperation between receptor signalling and genetic changes.

PMID: 29674500 [PubMed - as supplied by publisher]




True, true unrelated? Coexistence of Waldenstrom's macroglobulinemia and cardiac transthyretin Amyloidosis.
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True, true unrelated? Coexistence of Waldenstrom's macroglobulinemia and cardiac transthyretin Amyloidosis.

Haematologica. 2018 Apr 19;:

Authors: Singh A, Geller HI, Alexander KM, Padera RF, Mitchell RN, Dorbala S, Castillo JJ, Falk RH

PMID: 29674499 [PubMed - as supplied by publisher]




Microenvironmental M1 tumor-associated macrophage polarization influences cancer-related anemia in advanced ovarian cancer: key role of Interleukin-6.
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Microenvironmental M1 tumor-associated macrophage polarization influences cancer-related anemia in advanced ovarian cancer: key role of Interleukin-6.

Haematologica. 2018 Apr 19;:

Authors: Madeddu C, Gramignano G, Kotsonis P, Coghe F, Atzeni V, Scartozzi M, Macciò A

PMID: 29674498 [PubMed - as supplied by publisher]




Plasma cell proliferative index predicts outcome in immunoglobulin light chain amyloidosis treated with stem cell transplantation.
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Plasma cell proliferative index predicts outcome in immunoglobulin light chain amyloidosis treated with stem cell transplantation.

Haematologica. 2018 Apr 19;:

Authors: Sidiqi MH, Aljama M, Jevremovic D, Morice WG, Timm M, Buadi FK, Warsame R, Lacy MQ, Dispenzieri A, Dingli D, Gonsalves WI, Kumar S, Kapoor P, Kourelis T, Leung N, Hogan WJ, Gertz M

Abstract
The plasma cell proliferative index provides an insight into plasma cell biology in plasma cell disorders and is an important prognostic marker in myeloma and smoldering myeloma. We analyzed the prognostic impact of the plasma cell proliferative index in 513 patients with systemic AL Amyloidosis undergoing stem cell transplantation at the Mayo Clinic between January 2003 and 31 August 2016. Two cohorts were identified; Low or Elevated plasma cell proliferative index. Patients with an Elevated plasma cell proliferative index had more cardiac involvement (56% vs 44%; p=0.01), less renal involvement (55% vs 70%; p=0.001) and were more likely to have bone marrow plasma cells ≥ 10% (58% vs 32%, p<0.0001) compared to those with a Low plasma cell proliferative index. Both progression free survival and overall survival were lower in patients with an Elevated compared to Low plasma cell proliferative index (Median progression free survival 44 vs 95 months, p<0.0001 and Median overall survival 102 vs 143 months, p=0.0003). All-cause mortality at 100 days was higher in patients with an elevated plasma cell proliferative index (Elevated 10.3% vs Low 4.3%, p=0.008). On multivariate analysis Elevated plasma cell proliferative index was an independent prognostic factor for overall survival (Hazard ratio 1.5, 95% CI 1.1-2.1, p=0.021). The plasma cell proliferative index is an important prognostic tool in patients with AL Amyloidosis undergoing stem cell transplant.

PMID: 29674497 [PubMed - as supplied by publisher]




GFI1 is required for RUNX1/ETO positive acute myeloid leukemia.
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GFI1 is required for RUNX1/ETO positive acute myeloid leukemia.

Haematologica. 2018 Apr 19;:

Authors: Marneth AE, Botezatu L, Hönes JM, Israël JCL, Schütte J, Vassen L, Lams RF, Bergevoet SM, Groothuis L, Mandoli A, Martens JHA, Huls G, Jansen JH, Dührsen U, Berg T, Möröy T, Wichmann C, Lo MC, Zhang DE, van der Reijden BA, Khandanpour C

PMID: 29674496 [PubMed - as supplied by publisher]




Platelet Munc13-4 regulates hemostasis, thrombosis and airway inflammation.
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Platelet Munc13-4 regulates hemostasis, thrombosis and airway inflammation.

Haematologica. 2018 Apr 19;:

Authors: Cardenas EI, Breaux K, Da Q, Flores JR, Ramos MA, Tuvim MJ, Burns AR, Rumbaut RE, Adachi R

Abstract
Platelet degranulation is crucial for hemostasis and may participate in inflammation. Exocytosis in platelets is mediated by SNARE proteins and should be controlled by Munc13 proteins. We found that platelets express Munc13-2 and -4. We assessed platelet granule exocytosis in Munc13-2 and -4 global and conditional KO mice, and observed that deletion of Munc13-4 ablates dense granule release and indirectly impairs alpha granule exocytosis. We found no exocytic role for Munc13-2 in platelets, not even in the absence of Munc13-4. In vitro, Munc13-4-deficient platelets exhibited defective aggregation at low doses of collagen. In a flow chamber assay, we observed that Munc13-4 acted as a rate-limiting factor in the formation of thrombi. In vivo, we observed a dose-dependency between Munc13-4 expression in platelets and both venous bleeding time and time to arterial thrombosis. Finally, in a model of allergic airway inflammation, we found that platelet-specific Munc13-4 KO mice had a reduction in airway hyperresponsiveness and eosinophilic inflammation. Taken together, our results indicate that Munc13-4-dependent platelet dense granule release plays essential roles in hemostasis, thrombosis and allergic inflammation.

PMID: 29674495 [PubMed - as supplied by publisher]




Safety and efficacy of vorinostat, bortezomib, doxorubicin and dexamethasone in a phase I/II study for relapsed or refractory multiple myeloma (VERUMM study: vorinostat in elderly, relapsed and unfit multiple myeloma).
Related Articles

Safety and efficacy of vorinostat, bortezomib, doxorubicin and dexamethasone in a phase I/II study for relapsed or refractory multiple myeloma (VERUMM study: vorinostat in elderly, relapsed and unfit multiple myeloma).

Haematologica. 2018 Apr 19;:

Authors: Waldschmidt JM, Keller A, Ihorst G, Grishina O, Müller S, Wider D, Frey AV, King K, Simon R, May A, Tassone P, Duyster J, Jung M, Raje N, Wäsch R, Engelhardt M

Abstract
This phase I/II trial was conducted to investigate the safety, efficacy, and pharmacodynamics of the pan-HDAC-inhibitor (HDACi) vorinostat combined with bortezomib, doxorubicin, and dexamethasone (VBDD) in patients suffering from relapsed/refractory multiple myeloma (RRMM). In the phase I part of this study, 9/33 patients received dose-escalated vorinostat (100, 200, 300mg), using a 4-day-on and 4-day-off schedule, and a standard 3+3 design. In the phase II part of the study, 24/33 patients were included to further assess VBDD's safety and efficacy. Complementary analyses were performed throughout the trial to correlate clinical outcome with patient fitness, pharmacodynamics and potential biomarkers. The number of prior therapy lines was substantial with a median of 3 (1-9; prior bortezomib treatment: 88%). VBDD was well tolerated with no dose-limiting toxicity: 15 adverse events occurred in 9/33 (27%) patients. The best overall response rate was 67% and clinical benefit rate 94%. With a median follow-up of 30.8 months, median progression-free- and overall-survival were 9.6 and 33.8 months, respectively. VBDD-responders showed early pan-HDAC activity decreases in peripheral blood mononuclear cell samples (median 45% of pre-treatment levels), of bone marrow (BM) infiltration rates and of BM-HDAC6 expression. VBDD proved to be an effective, well-tolerated outpatient quadruplet regimen with promising responses in RRMM. Our intermittent HDACi schedule provides a novel treatment option as compared to previous maximum-tolerated-dose-driven HDACi approaches and may serve as a useful example for other HDACi combinations, demonstrating that a continuous epigenetic treatment, with proven synergy to antimyeloma agents, is relevant before HDACi are dismissed as antimyeloma agents.

PMID: 29674494 [PubMed - as supplied by publisher]