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Impact of constitutional TET2 haploinsufficiency on molecular and clinical phenotype in humans.

To, 21/03/2019 - 21:44
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Impact of constitutional TET2 haploinsufficiency on molecular and clinical phenotype in humans.

Nat Commun. 2019 Mar 19;10(1):1252

Authors: Kaasinen E, Kuismin O, Rajamäki K, Ristolainen H, Aavikko M, Kondelin J, Saarinen S, Berta DG, Katainen R, Hirvonen EAM, Karhu A, Taira A, Tanskanen T, Alkodsi A, Taipale M, Morgunova E, Franssila K, Lehtonen R, Mäkinen M, Aittomäki K, Palotie A, Kurki MI, Pietiläinen O, Hilpert M, Saarentaus E, Niinimäki J, Junttila J, Kaikkonen K, Vahteristo P, Skoda RC, Seppänen MRJ, Eklund KK, Taipale J, Kilpivaara O, Aaltonen LA

Abstract
Clonal hematopoiesis driven by somatic heterozygous TET2 loss is linked to malignant degeneration via consequent aberrant DNA methylation, and possibly to cardiovascular disease via increased cytokine and chemokine expression as reported in mice. Here, we discover a germline TET2 mutation in a lymphoma family. We observe neither unusual predisposition to atherosclerosis nor abnormal pro-inflammatory cytokine or chemokine expression. The latter finding is confirmed in cells from three additional unrelated TET2 germline mutation carriers. The TET2 defect elevates blood DNA methylation levels, especially at active enhancers and cell-type specific regulatory regions with binding sequences of master transcription factors involved in hematopoiesis. The regions display reduced methylation relative to all open chromatin regions in four DNMT3A germline mutation carriers, potentially due to TET2-mediated oxidation. Our findings provide insight into the interplay between epigenetic modulators and transcription factor activity in hematological neoplasia, but do not confirm the putative role of TET2 in atherosclerosis.

PMID: 30890702 [PubMed - in process]

Differences in the risk of stroke, bleeding events, and mortality between female and male patients with atrial fibrillation during warfarin therapy.

To, 21/03/2019 - 21:44
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Differences in the risk of stroke, bleeding events, and mortality between female and male patients with atrial fibrillation during warfarin therapy.

Eur Heart J Cardiovasc Pharmacother. 2019 01 01;5(1):29-36

Authors: Penttilä T, Lehto M, Niiranen J, Mehtälä J, Khanfir H, Lassila R, Raatikainen P

Abstract
Aims: Females with atrial fibrillation (AF) have been suggested to carry a higher risk for thromboembolic events than males. We compared the residual risk of stroke, bleeding events, and cardiovascular and all-cause mortality among female and male AF patients taking warfarin.
Methods and results: Data from several nationwide registries and laboratory databases were linked with the civil registration number of the patients. A total of 54 568 patients with data on the quality of warfarin treatment (time in therapeutic range) 60 days prior to the events were included (TTR60). Gender differences in the endpoints were reported for the whole population, pre-specified age groups, and different TTR60 groups. During the 3.2 ± 1.6 years follow-up, there were no differences in the adjusted risk of stroke [hazard ratio (HR) 0.97, 95% confidence interval (CI) 0.91-1.03, P = 0.304] between the genders. Cardiovascular mortality (HR 0.82, 95% CI 0.78-0.88, P < 0.001) and all-cause mortality (HR 0.79, 95% CI 0.75-0.83, P < 0.001) were lower in women when compared with men. There were no differences in the risk of stroke, cardiovascular mortality, and all-cause mortality between the genders in the TTR60 categories except for those with TTR60 <50%. Bleeding events were less frequent in females (HR 0.52, 95% CI 0.49-0.56, P < 0.001).
Conclusion: There were no differences in the risk of stroke between female and male AF patients taking warfarin. Cardiovascular mortality, all-cause mortality, and risk of bleeding events were lower in females. Hence, female gender was not a risk marker for adverse outcomes in AF patients with proper warfarin therapy.

PMID: 30052822 [PubMed - indexed for MEDLINE]

Allogeneic stem cell transplantation benefits for patients ≥ 60 years with acute myeloid leukemia and FLT3 internal tandem duplication: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

To, 21/03/2019 - 21:44
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Allogeneic stem cell transplantation benefits for patients ≥ 60 years with acute myeloid leukemia and FLT3 internal tandem duplication: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Haematologica. 2018 02;103(2):256-265

Authors: Poiré X, Labopin M, Polge E, Passweg J, Craddock C, Blaise D, Cornelissen JJ, Volin L, Russell NH, Socié G, Michallet M, Fegueux N, Chevallier P, Brecht A, Hunault-Berger M, Mohty M, Esteve J, Nagler A

Abstract
Intermediate-risk cytogenetic acute myeloid leukemia with an internal tandem duplication of FLT3 (FLT3-ITD) is associated with a high risk of relapse, and is now a standard indication for allogeneic stem cell transplantation. Nevertheless, most studies supporting this strategy have been performed in young patients. To address the benefit of allogeneic transplantation in the elderly, we made a selection from the European Society for Blood and Marrow Transplantation registry of de novo intermediate-risk cytogenetic acute myeloid leukemia harboring FLT3-ITD in patients aged 60 or over and transplanted from a related or unrelated donor between January 2000 and December 2015. Two hundred and ninety-one patients were identified. Most patients received a reduced-intensity conditioning (82%), while donors consisted of an unrelated donor in 161 (55%) patients. Two hundred and twelve patients received their transplantation in first remission, 37 in second remission and 42 in a more advanced stage of the disease. The 2-year leukemia-free survival rate was 56% in patients in first remission, 22% in those in second remission and 10% in patients with active disease, respectively (P<0.005). Non-relapse mortality for the entire cohort was 20%. In multivariate analysis, disease status at transplantation was the most powerful predictor of worse leukemia-free survival, graft-versus-host disease and relapse-free survival, and overall survival. In this elderly population, age was not associated with outcome. Based on the current results, allogeneic transplantation translates into a favorable outcome in fit patients ≥ 60 with FLT3-ITD acute myeloid leukemia in first remission, similarly to current treatment recommendations for younger patients.

PMID: 29242299 [PubMed - indexed for MEDLINE]

Somatic STAT3 mutations in Felty syndrome: an implication for a common pathogenesis with large granular lymphocyte leukemia.

To, 21/03/2019 - 21:44
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Somatic STAT3 mutations in Felty syndrome: an implication for a common pathogenesis with large granular lymphocyte leukemia.

Haematologica. 2018 02;103(2):304-312

Authors: Savola P, Brück O, Olson T, Kelkka T, Kauppi MJ, Kovanen PE, Kytölä S, Sokka-Isler T, Loughran TP, Leirisalo-Repo M, Mustjoki S

Abstract
Felty syndrome is a rare disease defined by neutropenia, splenomegaly, and rheumatoid arthritis. Sometimes the differential diagnosis between Felty syndrome and large granular lymphocyte leukemia is problematic. Recently, somatic STAT3 and STAT5B mutations were discovered in 30-40% of patients with large granular lymphocyte leukemia. Herein, we aimed to study whether these mutations can also be detected in Felty syndrome, which would imply the existence of a common pathogenic mechanism between these two disease entities. We collected samples and clinical information from 14 Felty syndrome patients who were monitored at the rheumatology outpatient clinic for Felty syndrome. Somatic STAT3 mutations were discovered in 43% (6/14) of Felty syndrome patients with deep amplicon sequencing targeting all STAT3 exons. Mutations were located in the SH2 domain of STAT3, which is a known mutational hotspot. No STAT5B mutations were found. In blood smears, overrepresentation of large granular lymphocytes was observed, and in the majority of cases the CD8+ T-cell receptor repertoire was skewed when analyzed by flow cytometry. In bone marrow biopsies, an increased amount of phospho-STAT3 positive cells was discovered. Plasma cytokine profiling showed that ten of the 92 assayed cytokines were elevated both in Felty syndrome and large granular lymphocyte leukemia, and three of these cytokines were also increased in patients with uncomplicated rheumatoid arthritis. In conclusion, somatic STAT3 mutations and STAT3 activation are as frequent in Felty syndrome as they are in large granular lymphocyte leukemia. Considering that the symptoms and treatment modalities are also similar, a unified reclassification of these two syndromes is warranted.

PMID: 29217783 [PubMed - indexed for MEDLINE]

Outcome after relapse of myelodysplastic syndrome and secondary acute myeloid leukemia following allogeneic stem cell transplantation: a retrospective registry analysis on 698 patients by the Chronic Malignancies Working Party of the European Society...

To, 21/03/2019 - 21:44
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Outcome after relapse of myelodysplastic syndrome and secondary acute myeloid leukemia following allogeneic stem cell transplantation: a retrospective registry analysis on 698 patients by the Chronic Malignancies Working Party of the European Society of Blood and Marrow Transplantation.

Haematologica. 2018 02;103(2):237-245

Authors: Schmid C, de Wreede LC, van Biezen A, Finke J, Ehninger G, Ganser A, Volin L, Niederwieser D, Beelen D, Alessandrino P, Kanz L, Schleuning M, Passweg J, Veelken H, Maertens J, Cornelissen JJ, Blaise D, Gramatzki M, Milpied N, Yakoub-Agha I, Mufti G, Rovira M, Arnold R, de Witte T, Robin M, Kröger N

Abstract
No standard exists for the treatment of myelodysplastic syndrome relapsing after allogeneic stem cell transplantation. We performed a retrospective registry analysis of outcomes and risk factors in 698 patients, treated with different strategies. The median overall survival from relapse was 4.7 months (95% confidence interval: 4.1-5.3) and the 2-year survival rate was 17.7% (95% confidence interval: 14.8-21.2%). Shorter remission after transplantation (P<0.001), advanced disease (P=0.001), older age (P=0.007), unrelated donor (P=0.008) and acute graft-versus-host disease before relapse (P<0.001) adversely influenced survival. At 6 months from relapse, patients had received no cellular treatment, (i.e. palliative chemotherapy or best supportive care, n=375), donor lymphocyte infusion (n=213), or a second transplant (n=110). Treatment groups were analyzed separately because of imbalanced characteristics and difficulties in retrospectively evaluating the reason for individual treatments. Of the patients who did not receive any cellular therapy, 109 were alive at 6 months after relapse, achieving a median overall survival from this landmark of 8.9 months (95% confidence interval: 5.1-12.6). Their 2-year survival rate was 29.7%. Recipients of donor lymphocytes achieved a median survival from first infusion of 6.0 months (95% confidence interval: 3.7-8.3) with a 2-year survival rate of 27.6%. Longer remission after first transplantation (P<0.001) and younger age (P=0.009) predicted better outcome. Among recipients of a second transplant, the median survival from second transplantation was 4.2 months (95% confidence interval: 2.5-5.9), and their 2-year survival rate was 17.0%. Longer remission after first transplantation (P<0.001), complete remission at second transplant (P=0.008), no prior chronic graft-versus-host disease (P<0.001) and change to a new donor (P=0.04) predicted better outcome. The data enabled identification of patients benefiting from donor lymphocyte infusion and second transplantation, and may serve as a baseline for prospective trials.

PMID: 29101205 [PubMed - indexed for MEDLINE]

Primary Polyomavirus Infection, Not Reactivation, as the Cause of Trichodysplasia Spinulosa in Immunocompromised Patients.

To, 21/03/2019 - 21:44
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Primary Polyomavirus Infection, Not Reactivation, as the Cause of Trichodysplasia Spinulosa in Immunocompromised Patients.

J Infect Dis. 2017 Apr 01;215(7):1080-1084

Authors: van der Meijden E, Horváth B, Nijland M, de Vries K, Rácz EK, Diercks GF, de Weerd AE, Clahsen-van Groningen MC, van der Blij-de Brouwer CS, van der Zon AJ, Kroes ACM, Hedman K, van Kampen JJA, Riezebos-Brilman A, Feltkamp MCW

Abstract
Classic human polyomaviruses (JC and BK viruses) become pathogenic when reactivating from latency. For the rare skin disease trichodysplasia spinulosa, we show that manifestations of the causative polyomavirus (TSPyV) occur during primary infection of the immunosuppressed host. High TSPyV loads in blood and cerebrospinal fluid, sometimes coinciding with cerebral lesions and neuroendocrine symptoms, marked the acute phase of trichodysplasia spinulosa, whereas initiation and maturation of TSPyV seroresponses occurred in the convalescent phase. TSPyV genomes lacked the rearrangements typical for reactivating polyomaviruses. These findings demonstrate the clinical importance of primary infection with this rapidly expanding group of human viruses and explain the rarity of some novel polyomavirus-associated diseases.

PMID: 27578847 [PubMed - indexed for MEDLINE]

Clinical Challenges: Identification of Patients With Novel Primary Immunodeficiency Syndromes.

Ke, 20/03/2019 - 21:44
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Clinical Challenges: Identification of Patients With Novel Primary Immunodeficiency Syndromes.

J Pediatr Hematol Oncol. 2018 07;40(5):e319-e322

Authors: Buchbinder D, Seppanen M, Rao VK, Uzel G, Nugent D

Abstract
Novel primary immunodeficiency disorders are being identified with next generation sequencing technologies. We describe 1 patient with cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) haploinsufficiency who had recurrent enhancing brain lesions, nodular pulmonary infiltrates, hepatosplenomegaly, immune cytopenias, as well as progressive hypogammaglobulinemia and lymphopenia. We describe a second patient with activated p110δ syndrome (APDS)/p110δ activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency (PASLI) in association with recurrent respiratory tract infections, Epstein-Barr virus infection, lymphadenopathy, elevated serum IgM, and progressive lymphopenia. These presentations highlight the need for astute clinical judgment in the evaluation of patients with potential primary immunodeficiency disorders.

PMID: 29200144 [PubMed - indexed for MEDLINE]

Diagnostics of rare disorders: whole-exome sequencing deciphering locus heterogeneity in telomere biology disorders.

Ti, 19/03/2019 - 21:44
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Diagnostics of rare disorders: whole-exome sequencing deciphering locus heterogeneity in telomere biology disorders.

Orphanet J Rare Dis. 2018 08 17;13(1):139

Authors: Trotta L, Norberg A, Taskinen M, Béziat V, Degerman S, Wartiovaara-Kautto U, Välimaa H, Jahnukainen K, Casanova JL, Seppänen M, Saarela J, Koskenvuo M, Martelius T

Abstract
BACKGROUND: The telomere biology disorders (TBDs) include a range of multisystem diseases characterized by mucocutaneous symptoms and bone marrow failure. In dyskeratosis congenita (DKC), the clinical features of TBDs stem from the depletion of crucial stem cell populations in highly proliferative tissues, resulting from abnormal telomerase function. Due to the wide spectrum of clinical presentations and lack of a conclusive laboratory test it may be challenging to reach a clinical diagnosis, especially if patients lack the pathognomonic clinical features of TBDs.
METHODS: Clinical sequencing was performed on a cohort of patients presenting with variable immune phenotypes lacking molecular diagnoses. Hypothesis-free whole-exome sequencing (WES) was selected in the absence of compelling diagnostic hints in patients with variable immunological and haematological conditions.
RESULTS: In four patients belonging to three families, we have detected five novel variants in known TBD-causing genes (DKC1, TERT and RTEL1). In addition to the molecular findings, they all presented shortened blood cell telomeres. These findings are consistent with the displayed TBD phenotypes, addressing towards the molecular diagnosis and subsequent clinical follow-up of the patients.
CONCLUSIONS: Our results strongly support the utility of WES-based approaches for routine genetic diagnostics of TBD patients with heterogeneous or atypical clinical presentation who otherwise might remain undiagnosed.

PMID: 30115091 [PubMed - indexed for MEDLINE]

Somatic late effects in 5-year survivors of neuroblastoma: a population-based cohort study within the Adult Life after Childhood Cancer in Scandinavia study.

Pe, 15/03/2019 - 21:43
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Somatic late effects in 5-year survivors of neuroblastoma: a population-based cohort study within the Adult Life after Childhood Cancer in Scandinavia study.

Int J Cancer. 2018 12 15;143(12):3083-3096

Authors: Norsker FN, Rechnitzer C, Cederkvist L, Holmqvist AS, Tryggvadottir L, Madanat-Harjuoja LM, Øra I, Thorarinsdottir HK, Vettenranta K, Bautz A, Schrøder H, Hasle H, Winther JF

Abstract
Because of the rarity of neuroblastoma and poor survival until the 1990s, information on late effects in neuroblastoma survivors is sparse. We comprehensively reviewed the long-term risk for somatic disease in neuroblastoma survivors. We identified 721 5-year survivors of neuroblastoma in Nordic population-based cancer registries and identified late effects in national hospital registries covering the period 1977-2012. Detailed treatment information was available for 46% of the survivors. The disease-specific rates of hospitalization of survivors and of 152,231 randomly selected population comparisons were used to calculate standardized hospitalization rate ratios (SHRRs) and absolute excess risks (AERs). During 5,500 person-years of follow-up, 501 5-year survivors had a first hospital contact yielding a SHRR of 2.3 (95% CI 2.1-2.6) and a corresponding AER of 52 (95% CI 44-60) per 1,000 person-years. The highest relative risks were for diseases of blood and blood-forming organs (SHRR 3.8; 95% CI 2.7-5.4), endocrine diseases (3.6 [3.1-4.2]), circulatory system diseases (3.1 [2.5-3.8]), and diseases of the nervous system (3.0 [2.6-3.3]). Approximately 60% of the excess new hospitalizations of survivors were for diseases of the nervous system, urinary system, endocrine system, and bone and soft tissue. The relative risks and AERs were highest for the survivors most intensively treated. Survivors of neuroblastoma have a highly increased long-term risk for somatic late effects in all the main disease groups as compared to background levels. Our results are useful for counseling survivors and should contribute to improving health care planning in post-therapy clinics.

PMID: 29926896 [PubMed - indexed for MEDLINE]

Characterization of polydactyly chondrocytes and their use in cartilage engineering.

To, 14/03/2019 - 21:43
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Characterization of polydactyly chondrocytes and their use in cartilage engineering.

Sci Rep. 2019 Mar 12;9(1):4275

Authors: Cavalli E, Levinson C, Hertl M, Broguiere N, Brück O, Mustjoki S, Gerstenberg A, Weber D, Salzmann G, Steinwachs M, Barreto G, Zenobi-Wong M

Abstract
Treating cartilage injuries and degenerations represents an open surgical challenge. The recent advances in cell therapies have raised the need for a potent off-the-shelf cell source. Intra-articular injections of TGF-β transduced polydactyly chondrocytes have been proposed as a chronic osteoarthritis treatment but despite promising results, the use of gene therapy still raises safety concerns. In this study, we characterized infant, polydactyly chondrocytes during in vitro expansion and chondrogenic re-differentiation. Polydactyly chondrocytes have a steady proliferative rate and re-differentiate in 3D pellet culture after up to five passages. Additionally, we demonstrated that polydactyly chondrocytes produce cartilage-like matrix in a hyaluronan-based hydrogel, namely transglutaminase cross-linked hyaluronic acid (HA-TG). We utilized the versatility of TG cross-linking to augment the hydrogels with heparin moieties. The heparin chains allowed us to load the scaffolds with TGF-β1, which induced cartilage-like matrix deposition both in vitro and in vivo in a subcutaneous mouse model. This strategy introduces the possibility to use infant, polydactyly chondrocytes for the clinical treatment of joint diseases.

PMID: 30862915 [PubMed - in process]

Interrogation of human hematopoiesis at single-cell and single-variant resolution.

Ke, 13/03/2019 - 21:43
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Interrogation of human hematopoiesis at single-cell and single-variant resolution.

Nat Genet. 2019 Mar 11;:

Authors: Ulirsch JC, Lareau CA, Bao EL, Ludwig LS, Guo MH, Benner C, Satpathy AT, Kartha VK, Salem RM, Hirschhorn JN, Finucane HK, Aryee MJ, Buenrostro JD, Sankaran VG

Abstract
Widespread linkage disequilibrium and incomplete annotation of cell-to-cell state variation represent substantial challenges to elucidating mechanisms of trait-associated genetic variation. Here we perform genetic fine-mapping for blood cell traits in the UK Biobank to identify putative causal variants. These variants are enriched in genes encoding proteins in trait-relevant biological pathways and in accessible chromatin of hematopoietic progenitors. For regulatory variants, we explore patterns of developmental enhancer activity, predict molecular mechanisms, and identify likely target genes. In several instances, we localize multiple independent variants to the same regulatory element or gene. We further observe that variants with pleiotropic effects preferentially act in common progenitor populations to direct the production of distinct lineages. Finally, we leverage fine-mapped variants in conjunction with continuous epigenomic annotations to identify trait-cell type enrichments within closely related populations and in single cells. Our study provides a comprehensive framework for single-variant and single-cell analyses of genetic associations.

PMID: 30858613 [PubMed - as supplied by publisher]

Standardisation and consensus guidelines for minimal residual disease assessment in Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL) by real-time quantitative reverse transcriptase PCR of e1a2 BCR-ABL1.

Ke, 13/03/2019 - 21:43
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Standardisation and consensus guidelines for minimal residual disease assessment in Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL) by real-time quantitative reverse transcriptase PCR of e1a2 BCR-ABL1.

Leukemia. 2019 Mar 11;:

Authors: Pfeifer H, Cazzaniga G, van der Velden VHJ, Cayuela JM, Schäfer B, Spinelli O, Akiki S, Avigad S, Bendit I, Borg K, Cavé H, Elia L, Reshmi SC, Gerrard G, Hayette S, Hermanson M, Juh A, Jurcek T, Chillón MC, Homburg C, Martinelli G, Kairisto V, Lange T, Lion T, Mueller MC, Pane F, Rai L, Damm-Welk C, Sacha T, Schnittger S, Touloumenidou T, Valerhaugen H, Vandenberghe P, Zuna J, Serve H, Herrmann E, Markovic S, Dongen JJMV, Ottmann OG

Abstract
Minimal residual disease (MRD) is a powerful prognostic factor in acute lymphoblastic leukemia (ALL) and is used for patient stratification and treatment decisions, but its precise role in Philadelphia chromosome positive ALL is less clear. This uncertainty results largely from methodological differences relating to the use of real-time quantitative PCR (qRT-PCR) to measure BCR-ABL1 transcript levels for MRD analysis. We here describe the first results by the EURO-MRD consortium on standardization of qRT-PCR for the e1a2 BCR-ABL1 transcript in Ph + ALL, designed to overcome the lack of standardisation of laboratory procedures and data interpretation. Standardised use of EAC primer/probe sets and of centrally prepared plasmid standards had the greatest impact on reducing interlaboratory variability. In QC1 the proportion of analyses with BCR-ABL1/ABL1 ratios within half a log difference were 40/67 (60%) and 52/67 (78%) at 10-3 and 36/67 (53%) and 53/67 (79%) at 10-4BCR-ABL1/ABL1. Standardized RNA extraction, cDNA synthesis and cycler platforms did not improve results further, whereas stringent application of technical criteria for assay quality and uniform criteria for data interpretation and reporting were essential. We provide detailed laboratory recommendations for the standardized MRD analysis in routine diagnostic settings and in multicenter clinical trials for Ph + ALL.

PMID: 30858550 [PubMed - as supplied by publisher]

Use of granulocyte colony-stimulating factor and risk of relapse in pediatric patients treated for acute myeloid leukemia according to NOPHO-AML 2004 and DB AML-01.

La, 09/03/2019 - 21:42
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Use of granulocyte colony-stimulating factor and risk of relapse in pediatric patients treated for acute myeloid leukemia according to NOPHO-AML 2004 and DB AML-01.

Pediatr Blood Cancer. 2019 Mar 07;:e27701

Authors: Løhmann DJA, Asdahl PH, Abrahamsson J, Ha SY, Jónsson ÓG, Kaspers GJL, Koskenvuo M, Lausen B, De Moerloose B, Palle J, Zeller B, Hasle H

Abstract
BACKGROUND: Supportive-care use of granulocyte colony-stimulating factor (G-CSF) in pediatric acute myeloid leukemia (AML) remains controversial due to a theoretical increased risk of relapse and limited impact on neutropenic complications. We describe the use of G-CSF in patients treated according to NOPHO-AML 2004 and DB AML-01 and investigated associations with relapse.
PROCEDURE: Patients diagnosed with de novo AML completing the first week of therapy and not treated with hematopoietic stem cell transplantation in the first complete remission were included (n = 367). Information on G-CSF treatment after each course (yes/no) was registered prospectively in the study database and detailed information was gathered retrospectively from each center. Descriptive statistics were used to describe G-CSF use and Cox regression to assess the association between G-CSF and risk of relapse.
RESULTS: G-CSF as supportive care was given to 128 (35%) patients after 268 (39%) courses, with a large variation between centers (0-93%). The use decreased with time-the country-adjusted odds ratio was 0.8/diagnostic year (95% confidence interval [CI] 0.7-0.9). The median daily dose was 5 μg/kg (range 3-12 μg/kg) and the median cumulative dose was 75 μg/kg (range 7-1460 μg/kg). Filgrastim was used in 82% of G-CSF administrations and infection was the indication in 44% of G-CSF administrations. G-CSF was associated with increased risk of relapse-the adjusted hazard ratio was 1.5 (95% CI 1.1-2.2).
CONCLUSIONS: G-CSF as supportive care was used in a third of patients, and use decreased with time. Our results indicate that the use of G-CSF may be associated with an increased risk of relapse.

PMID: 30848067 [PubMed - as supplied by publisher]

Prognostic significance of recurring chromosomal abnormalities in transplanted patients with acute myeloid leukemia.

La, 09/03/2019 - 21:42
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Prognostic significance of recurring chromosomal abnormalities in transplanted patients with acute myeloid leukemia.

Leukemia. 2019 Mar 07;:

Authors: Canaani J, Labopin M, Itälä-Remes M, Blaise D, Socié G, Forcade E, Maertens J, Wu D, Malladi R, Cornelissen JJ, Huynh A, Bourhis JH, Esteve J, Mohty M, Nagler A

Abstract
Baseline cytogenetic studies at diagnosis remain the single most important determinant of outcome in patients with acute myeloid leukemia (AML). However, the prognostic role of the complete gamut of cytogenetic aberrations in AML patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently undefined. In addition, their significance in conjunction with FLT3-ITD status has not been addressed thus far. Using the ALWP/EBMT registry we conducted a retrospective analysis to determine the clinical outcomes of AML patients undergoing allo-HSCT with respect to specific recurring cytogenetic abnormalities complemented with FLT3-ITD status. We analyzed a cohort consisting of 8558 adult AML patients who underwent allo-HSCT from either a matched sibling or a matched unrelated donor. Patients with inv(3)(q21q26)/t(3;3)(q21;q26), del(5q), monosomy 7, chromosome 17p abnormalities, t(10;11)(p11-14;q13-23), t(6;11)(q27;q23), as well as those patients with a monosomal or complex karyotype experienced significantly inferior leukemia-free survival (LFS) compared to patients with a normal karyotype. Trisomy 14, del(9q), and loss of chromosome X were associated with improved LFS rates. A novel prognostic model delineating 5 distinct groups incorporating cytogenetic complexity and FLT3-ITD status was constructed with significant prognostic implications. Our analysis supports the added prognostic significance of FLT3-ITD to baseline cytogenetics in patients undergoing allo-HSCT.

PMID: 30846862 [PubMed - as supplied by publisher]

European expert consensus statement on therapeutic goals in Fabry disease.

La, 09/03/2019 - 21:42
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European expert consensus statement on therapeutic goals in Fabry disease.

Mol Genet Metab. 2018 07;124(3):189-203

Authors: Wanner C, Arad M, Baron R, Burlina A, Elliott PM, Feldt-Rasmussen U, Fomin VV, Germain DP, Hughes DA, Jovanovic A, Kantola I, Linhart A, Mignani R, Monserrat L, Namdar M, Nowak A, Oliveira JP, Ortiz A, Pieroni M, Spada M, Tylki-Szymańska A, Tøndel C, Viana-Baptista M, Weidemann F, Hilz MJ

Abstract
BACKGROUND: Fabry disease, an inherited lysosomal storage disorder, causes multi-organ pathology resulting in substantial morbidity and a reduced life expectancy. Although Fabry disease is an X-linked disorder, both genders may be affected, but generally to a lesser extent in females. The disease spectrum ranges from classic early-onset disease to non-classic later-onset phenotypes, with complications occurring in multiple organs or being confined to a single organ system depending on the stage of the disease. The impact of therapy depends upon patient- and disease-specific factors and timing of initiation.
METHODS: A European panel of experts collaborated to develop a set of organ-specific therapeutic goals for Fabry disease, based on evidence identified in a recent systematic literature review and consensus opinion.
RESULTS: A series of organ-specific treatment goals were developed. For each organ system, optimal treatment strategies accounted for inter-patient differences in disease severity, natural history, and treatment responses as well as the negative burden of therapy and the importance of multidisciplinary care. The consensus therapeutic goals and proposed patient management algorithm take into account the need for early disease-specific therapy to delay or slow the progression of disease as well as non-specific adjunctive therapies that prevent or treat the effects of organ damage on quality of life and long-term prognosis.
CONCLUSIONS: These consensus recommendations help advance Fabry disease management by considering the balance between anticipated clinical benefits and potential therapy-related challenges in order to facilitate individualized treatment, optimize patient care and improve quality of life.

PMID: 30017653 [PubMed - indexed for MEDLINE]

Diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in pediatric patients: a new classification from the European society for blood and marrow transplantation.

La, 09/03/2019 - 21:42
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Diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in pediatric patients: a new classification from the European society for blood and marrow transplantation.

Bone Marrow Transplant. 2018 02;53(2):138-145

Authors: Corbacioglu S, Carreras E, Ansari M, Balduzzi A, Cesaro S, Dalle JH, Dignan F, Gibson B, Guengoer T, Gruhn B, Lankester A, Locatelli F, Pagliuca A, Peters C, Richardson PG, Schulz AS, Sedlacek P, Stein J, Sykora KW, Toporski J, Trigoso E, Vetteranta K, Wachowiak J, Wallhult E, Wynn R, Yaniv I, Yesilipek A, Mohty M, Bader P

Abstract
The advances in hematopoietic cell transplantation (HCT) over the last decade have led to a transplant-related mortality below 15%. Hepatic sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is a life-threatening complication of HCT that belongs to a group of diseases increasingly identified as transplant-related, systemic endothelial diseases. In most cases, SOS/VOD resolves within weeks; however, severe SOS/VOD results in multi-organ dysfunction/failure with a mortality rate >80%. A timely diagnosis of SOS/VOD is of critical importance, given the availability of therapeutic options with favorable tolerability. Current diagnostic criteria are used for adults and children. However, over the last decade it has become clear that SOS/VOD is significantly different between the age groups in terms of incidence, genetic predisposition, clinical presentation, prevention, treatment and outcome. Improved understanding of SOS/VOD and the availability of effective treatment questions the use of the Baltimore and Seattle criteria for diagnosing SOS/VOD in children. The aim of this position paper is to propose new diagnostic and severity criteria for SOS/VOD in children on behalf of the European Society for Blood and Marrow Transplantation.

PMID: 28759025 [PubMed - indexed for MEDLINE]

Platelets compensate for poor thrombin generation in type 3 von Willebrand disease.

To, 07/03/2019 - 21:42
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Platelets compensate for poor thrombin generation in type 3 von Willebrand disease.

Platelets. 2019 Mar 05;:1-9

Authors: Szanto T, Nummi V, Jouppila A, Brinkman HJM, Lassila R

Abstract
In type 3 von Willebrand disease (VWD3), the most severe form with absent von Willebrand factor (VWF), the bleeding phenotype is variable. Platelet contribution to the hemostatic defect in VWD3 calls upon further studies. We investigated the contribution of platelets to in vitro thrombin generation (TG) and platelet procoagulant activity in VWD3. TG was assessed by calibrated automated thrombogram (CAT) in platelet-poor (PPP) and -rich plasma (PRP) from 9 patients before and in 6 patients also 30 min after receiving their regular VWF therapy. Responsiveness of PPP to FVIII and protein S was also investigated. TG data were compared with routine laboratory variables, rotational thromboelastometry (ROTEM) and platelet expression of P-selectin and phosphatidylserine in flow cytometry. Compared with healthy controls, TG was markedly decreased in VWD3 PPP (peak thrombin was 16% of normal median), but not in PRP (77% of normal median) (p = 0.002). Six out of nine patients (67%) were high responders in their platelet P-selectin, and 5/9 (56%) in phosphatidylserine expression. Replacement therapy improved TG in PPP, while in PRP TG only modestly increased or was unaffected. In PPP, FVIII levels associated with TG and in vitro FVIII-supplemented TG inclined up to threefold. Conversely, a FVIII inhibitory antibody reduced plasma TG in all, but especially in patients with remnant FVIII levels. Inhibition of protein S improved plasma TG, particularly at low FVIII levels. ROTEM failed to detect VWD3. In VWD3, TG is reduced in PPP and regulated by FVIII and protein S, but TG is close to normal in PRP. VWD3 platelets seem to compensate for the FVIII-associated reduction in TG by their exposure of P-selectin and phosphatidylserine.

PMID: 30836803 [PubMed - as supplied by publisher]

CD36 defines primitive chronic myeloid leukemia cells less responsive to imatinib but vulnerable to antibody-based therapeutic targeting.

To, 07/03/2019 - 21:42
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CD36 defines primitive chronic myeloid leukemia cells less responsive to imatinib but vulnerable to antibody-based therapeutic targeting.

Haematologica. 2018 03;103(3):447-455

Authors: Landberg N, von Palffy S, Askmyr M, Lilljebjörn H, Sandén C, Rissler M, Mustjoki S, Hjorth-Hansen H, Richter J, Ågerstam H, Järås M, Fioretos T

Abstract
Tyrosine kinase inhibitors (TKIs) are highly effective for the treatment of chronic myeloid leukemia (CML), but very few patients are cured. The major drawbacks regarding TKIs are their low efficacy in eradicating the leukemic stem cells responsible for disease maintenance and relapse upon drug cessation. Herein, we performed ribonucleic acid sequencing of flow-sorted primitive (CD34+CD38low) and progenitor (CD34+ CD38+) chronic phase CML cells, and identified transcriptional upregulation of 32 cell surface molecules relative to corresponding normal bone marrow cells. Focusing on novel markers with increased expression on primitive CML cells, we confirmed upregulation of the scavenger receptor CD36 and the leptin receptor by flow cytometry. We also delineate a subpopulation of primitive CML cells expressing CD36 that is less sensitive to imatinib treatment. Using CD36 targeting antibodies, we show that the CD36 positive cells can be targeted and killed by antibody-dependent cellular cytotoxicity. In summary, CD36 defines a subpopulation of primitive CML cells with decreased imatinib sensitivity that can be effectively targeted and killed using an anti-CD36 antibody.

PMID: 29284680 [PubMed - indexed for MEDLINE]

Prospective, randomized, double-blinded, placebo-controlled study on safety and tolerability of the krill powder product in overweight subjects with moderately elevated blood pressure.

Ke, 06/03/2019 - 21:41
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Prospective, randomized, double-blinded, placebo-controlled study on safety and tolerability of the krill powder product in overweight subjects with moderately elevated blood pressure.

Lipids Health Dis. 2018 Dec 20;17(1):287

Authors: Sarkkinen ES, Savolainen MJ, Taurio J, Marvola T, Bruheim I

Abstract
BACKGROUND: Krill powder is rich in bioactive ingredients such as eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), phospholipids, protein and astaxanthin. Containing dominantly EPA, it is considered to be effective in lowering lipids, foremost serum triglycerides and LDL cholesterol. Krill-derived protein hydrolysates/peptides may have positive effect on blood pressure and astaxanthin has anti-oxidative and anti-inflammatory properties. Thus, krill powder has a lot of potential in improving lipid and metabolic profile and reinforcing the activity of the antioxidant system. However, randomized clinical trials on krill powder are scarce and systematic data of krill meal on human safety is limited. Some of the earlier studies have reported several, non-serious adverse events, mostly related to gastrointestinal tract, but systematic sufficiently powered study on safety is lacking. The aim of this study was to collect data on safety and tolerability of krill powder in humans and simultaneously gain efficacy data by measuring the risk factors for cardiovascular disease.
METHODS: The study was a randomised, double-blinded, placebo-controlled intervention study with 35 overweight subjects with mildly or moderately elevated blood pressure, who took 4 g krill oil powder or 4 g of placebo during an 8-week follow-up period. The study consisted of a pre-screening, screening, day 0 baseline (randomization visit) and three follow-up visits on days 14, 28 and 56. The reported adverse events in the groups were compared as primary endpoint and haematological safety parameters and changes in systolic and diastolic pressure and blood total and lipoprotein lipids were measured as secondary end points.
RESULTS: There were in total 80 reported adverse events during the follow-up; 50 in placebo and 30 in krill powder group. Gastrointestinal symptoms (flatulence, heartburn and diarrhea) were the most commonly reported among those probably related to the test products. No serious adverse events were reported. The mean value of all measured hematology variables remained within the reference values in all study subject and no significant changes were observed in blood pressure or lipid values.
CONCLUSIONS: The results seem to indicate that using krill powder as a source for EPA and DHA is safe in therapeutic dose and the risk of adverse events, let alone serious ones, is low.
TRIAL REGISTRATION: ClinicalTrials.gov, NCT03112083 , retrospectively registered.

PMID: 30572894 [PubMed - indexed for MEDLINE]

Placenta-mediated pregnancy complications are not associated with fetal or paternal factor V Leiden mutation.

Ke, 06/03/2019 - 21:41
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Placenta-mediated pregnancy complications are not associated with fetal or paternal factor V Leiden mutation.

Eur J Obstet Gynecol Reprod Biol. 2018 Nov;230:32-35

Authors: Nevalainen J, Ignatius J, Savolainen ER, Ryynanen M, Jarvenpaa J

Abstract
OBJECTIVE: Maternal thrombophilia is a risk factor for adverse pregnancy outcomes. The aim of this study was to elucidate the controversial role of fetal and paternal thrombophilia in the development of severe placenta-mediated pregnancy complications.
STUDY DESIGN: The study group comprised 126 mothers, 72 fetuses and 58 fathers. 111 mothers, 50 fetuses and 91 fathers acted as controls. 106 couples were selected to study the thrombophilias of paternal inheritance, 58 from the study group and 48 from the control group. The prevalence of factor V Leiden mutation, prothrombin G20210 A mutation and homozygous 10-methylenetetrahydrofolate reductase C677 T mutations were compared between the study and control groups to study whether maternal, fetal or paternal thrombophilias increase the risk of severe preeclampsia, intrauterine growth restriction, placental abruption and stillbirth.
RESULTS: The total prevalence of fetal thrombophilic mutations was 8.3% in the study group and 14.0% in the control group. Paternal prevalence of thrombophilic mutations was 6.8% and 4.3%, respectively. There were no statistical differences between fetal or paternal thrombophilic mutations between the study and control groups.
CONCLUSION: Fetal or paternal factor V Leiden mutation is not associated with severe placenta-mediated pregnancy complications.

PMID: 30243226 [PubMed - indexed for MEDLINE]