Subscribe to syöte PubMed PubMed
NCBI: db=pubmed; Term=(finland) AND hematology
Syötteen kokonainen osoite. 6 min 35 s sitten

Long-term clinical and economic outcomes in previously untreated paediatric patients with severe haemophilia A: A nationwide real-world study with 700 person-years.

La, 10/11/2018 - 21:15
Related Articles

Long-term clinical and economic outcomes in previously untreated paediatric patients with severe haemophilia A: A nationwide real-world study with 700 person-years.

Haemophilia. 2018 May;24(3):436-444

Authors: Vepsäläinen K, Riikonen P, Lassila R, Arola M, Huttunen P, Lähteenmäki P, Möttönen M, Selander T, Martikainen J

Abstract
AIM: For previously untreated patients (PUPs) with severe haemophilia A in Finland for the past 2 decades, the standard practice has been to start early primary prophylaxis. We evaluated the long-term clinical outcomes and costs of treatment with high-dose prophylaxis in PUPs from birth to adolescence, including immune tolerance induction (ITI).
METHODS: From the medical records of all PUPs born between June 1994 and May 2013 in Finland, we retrospectively extracted data on clinical outcomes and healthcare use. Using linear mixed models, we analysed longitudinal clinical outcome data. To analyse skewed cost data, including zero costs, we applied hurdle regression.
RESULTS: All 62 patients received early regular prophylaxis; totally, they have had treatment for nearly 700 patient-years. The median age of starting home treatment was 1.1 years. The mean (SD) annual treatment costs (€ per kg) were 4391€ (3852). For ages 1-3, ITI comprised over half of the costs; in other groups, prophylactic FVIII treatment dominated. With these high costs, however, clinical outcomes were desirable; median (IQR) ABR was low at 0.19 (0.07-0.46) and so was AJBR at 0.06 (0-0.24). Thirteen (21%) patients developed a clinically significant inhibitor, 10 (16%) with a high titre. All ITIs were successful. The mean costs for ITI were 383 448€ (259 085). The expected ITI payback period was 1.81 (95% CI 0.62-12.12) years.
CONCLUSIONS: Early high-dose prophylaxis leads to excellent long-term clinical outcomes, and early childhood ITI therapy seems to turn cost-neutral generally already in 2 years.

PMID: 29493848 [PubMed - indexed for MEDLINE]

Short-term side effects and attitudes towards second donation: A comparison of related and unrelated haematopoietic stem cell donors.

La, 10/11/2018 - 21:15
Related Articles

Short-term side effects and attitudes towards second donation: A comparison of related and unrelated haematopoietic stem cell donors.

J Clin Apher. 2018 Jun;33(3):226-235

Authors: Pahnke S, Larfors G, Axdorph-Nygell U, Fischer-Nielsen A, Haastrup E, Heldal D, Itälä-Remes M, Johansson JE, Kauppila M, Lenhoff S, Ljungman P, Niittyvuopio R, Sandstedt A, Hägglund H

Abstract
The Nordic Register of Haematopoietic Stem Cell Donors (NRHSD) has registered related and unrelated donors from 10 transplant centres in Sweden, Norway, Finland and Denmark since 1998. We present a prospective, observational study of 1,957 donors, focusing mainly on the differences between related and unrelated donors. Related donors are reported to have more comorbidities, but similar side effects compared with unrelated donors. Side effects after BM or PBSC donation are generally of short duration and in this study no deaths, myocardial infarctions, splenic ruptures, or thromboembolic events are reported. Interestingly, related donors express more hesitancy towards donating again when asked 1 month after donation.

PMID: 28833474 [PubMed - indexed for MEDLINE]

Family mismatched allogeneic stem cell transplantation for Myelofibrosis: Report from the Chronic Malignancies Working Party of EBMT.

Pe, 09/11/2018 - 21:14
Related Articles

Family mismatched allogeneic stem cell transplantation for Myelofibrosis: Report from the Chronic Malignancies Working Party of EBMT.

Biol Blood Marrow Transplant. 2018 Nov 05;:

Authors: Raj K, Eikema DJ, McLornan DP, Olavarria E, Blok HJ, Bregante S, Ciceri F, Passweg J, Ljungman P, Schaap N, Carlson K, Zuckerman T, de Wreede LC, Volin L, Koc Y, Diez-Martin J, Brossart P, Wolf D, Blaise D, Bartolomeo PD, Vitek A, Robin M, I YA, Chalandon Y, Kroger N

Abstract
This analysis includes 56 Myelofibrosis (MF) patients transplanted from family mismatched donor between 2009-2015 enrolled in the European Society for Blood and Marrow Transplantation (EBMT) database. The median age was 57 years (range, 38-72); 75% had primary MF and 25% had secondary MF. JAK2 V617F was mutated in 61%. Donors were HLA mismatched at 2 or more loci. Stem cells were sourced from bone marrow in 66% and peripheral blood in 34%. The median CD34+ cell dose was 4.8 × 106/kg (1.7-22.9 × 106/kg) (n=43). Conditioning was predominantly myeloablative (MAC) in 70% and reduced intensity (RIC) in the remainder. Regimens were heterogeneous with Thiotepa, Busulphan Fludarabine (TBF) and post-transplant cyclophosphamide (PTCy) used in 59%. The incidence of neutrophil engraftment by 28 days was 82% (range, 70-93%), at a median of 21 days (range,19-23). At 2 yrs. the CI of primary Graft failure was 9% (1-16%) and secondary graft failure was 13% (4-22%).The cumulative incidence (CI) of grades II-IV acute GvHD (aGvHD) and III-IV was 28% (16-40%) and 9% (2-17%) at 100 days. The CI of chronic GvHD (cGvHD) at 1 year was 45% (32-58%) but CI of death without cGVHD by 1 year was 20% (10-31%). With a median follow up of 32 months, the 1- and 2-year OS was 61% (48-74%) and 56% (41-70%) respectively. The 1- and 2- year PFS was 58% (45-71%) and 43% (28-58%) with a 2-year CI of relapse of 19% (7-31%). The 2-year non-relapse mortality (NRM) was 38% (24-51%). This retrospective study of MF allo-SCT utilising family mismatched donors, demonstrates feasibility of the approach, timely neutrophil engraftment in over 80% of cases and acceptable OS and PFS rates with relapse rates not dissimilar to the unrelated donor setting. However, strategies to minimise the risk of graft failure and the relatively high NRM need to be employed, ideally in a multicentre prospective fashion.

PMID: 30408564 [PubMed - as supplied by publisher]

Complex and monosomal karyotype are distinct cytogenetic entities with an adverse prognostic impact in paediatric acute myeloid leukaemia. A NOPHO-DBH-AML study.

Pe, 09/11/2018 - 21:14
Related Articles

Complex and monosomal karyotype are distinct cytogenetic entities with an adverse prognostic impact in paediatric acute myeloid leukaemia. A NOPHO-DBH-AML study.

Br J Haematol. 2018 Nov 08;:

Authors: Bager N, Juul-Dam KL, Sandahl JD, Abrahamsson J, Beverloo B, de Bont ESJM, Ha SY, Jahnukainen K, Jónsson ÓG, Kaspers GL, Kovalova Z, Lausen B, De Moerloose B, Noren-Nyström U, Palle J, Saks K, Zeller B, Kjeldsen E, Hasle H

Abstract
Data on occurrence, genetic characteristics and prognostic impact of complex and monosomal karyotype (CK/MK) in children with acute myeloid leukaemia (AML) are scarce. We studied CK and MK in a large unselected cohort of childhood AML patients diagnosed and treated according to Nordic Society for Paediatric Haematology and Oncology (NOPHO)-AML protocols 1993-2015. In total, 800 patients with de novo AML were included. CK was found in 122 (15%) and MK in 41 (5%) patients. CK and MK patients were young (median age 2·1 and 3·3 years, respectively) and frequently had FAB M7 morphology (24% and 22%, respectively). Refractory disease was more common in MK patients (15% vs. 4%) and stem cell transplantation in first complete remission was more frequent (32% vs. 19%) compared with non-CK/non-MK patients. CK showed no association with refractory disease but was an independent predictor of an inferior event-free survival (EFS; hazard ratio [HR] 1·43, P = 0·03) and overall survival (OS; HR 1·48, P = 0·01). MK was associated with a poor EFS (HR 1·57, P = 0·03) but did not show an inferior OS compared to non-MK patients (HR 1·14, P = 0·62). In a large paediatric cohort, we characterized AML with non-recurrent abnormal karyotype and unravelled the adverse impact of CK and MK on prognosis.

PMID: 30406946 [PubMed - as supplied by publisher]

Anticancer effect of pan-PI3K inhibitor on multiple myeloma cells: Shedding new light on the mechanisms involved in BKM120 resistance.

To, 08/11/2018 - 21:14
Related Articles

Anticancer effect of pan-PI3K inhibitor on multiple myeloma cells: Shedding new light on the mechanisms involved in BKM120 resistance.

Eur J Pharmacol. 2018 Oct 27;842:89-98

Authors: Safaroghli-Azar A, Bashash D, Kazemi A, Pourbagheri-Sigaroodi A, Momeny M

Abstract
The correlation between the Phosphoinositide 3-kinase (PI3K) axis and crucial mechanisms involved in the maintenance of the neoplastic nature of multiple myeloma (MM) has recently evolved a general agreement that PI3K inhibition-based therapies could construct an exciting perspective for the future treatment strategies. Our results outlined that abrogation of PI3K using pan-PI3K inhibitor BKM120 decreased survival of MM cells through induction of a caspase-3-dependent apoptosis coupled with SIRT1-mediated G2/M arrest in both KMM-1 and RPMI 8226 cell lines; however, the cell responses to the inhibitor was quite different, introducing wild-type PTEN-expressing RPMI 8226 as less sensitive cells. By investigating the sensitivity extent of a panel of hematological cell lines to BKM120, we found no significant association with respect to PTEN status. As far as we are aware, the results of the present study propose for the first time that the inhibitory effect of BKM120 was overshadowed, at least partially, through over-expression of either c-Myc or nuclear factor (NF)-κB in less sensitive MM cells. While there was no significant effect of the inhibitor on the expression of c-Myc in RPMI 8226, we found an enhanced cytotoxic effect when BKM120 was used in combination with a small molecule inhibitor of c-Myc. Noteworthy, the results of the synergistic experiments also revealed that BKM120 could produce a synergistic anti-cancer effect with carfilzomib (CFZ) and provided an enhanced therapeutic efficacy in MM cells, highlighting that PI3K inhibition might be a befitting approach in MM both in mono and combined therapy.

PMID: 30401630 [PubMed - as supplied by publisher]

HIV Activates the Tyrosine Kinase Hck to Secrete ADAM Protease-Containing Extracellular Vesicles.

To, 08/11/2018 - 21:14
Related Articles

HIV Activates the Tyrosine Kinase Hck to Secrete ADAM Protease-Containing Extracellular Vesicles.

EBioMedicine. 2018 02;28:151-161

Authors: Lee JH, Ostalecki C, Zhao Z, Kesti T, Bruns H, Simon B, Harrer T, Saksela K, Baur AS

PMID: 29331674 [PubMed - indexed for MEDLINE]

Hematopoietic stem cell transplantation for adults with Philadelphia chromosome-negative acute lymphoblastic leukemia in first remission: a position statement of the European Working Group for Adult Acute Lymphoblastic Leukemia (EWALL) and the Acute...

La, 03/11/2018 - 21:13
Related Articles

Hematopoietic stem cell transplantation for adults with Philadelphia chromosome-negative acute lymphoblastic leukemia in first remission: a position statement of the European Working Group for Adult Acute Lymphoblastic Leukemia (EWALL) and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT).

Bone Marrow Transplant. 2018 Nov 01;:

Authors: Giebel S, Marks DI, Boissel N, Baron F, Chiaretti S, Ciceri F, Cornelissen JJ, Doubek M, Esteve J, Fielding A, Foa R, Gorin NC, Gökbuget N, Hallböök H, Hoelzer D, Paravichnikova E, Ribera JM, Savani B, Rijneveld AW, Schmid C, Wartiovaara-Kautto U, Mohty M, Nagler A, Dombret H

Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission is a standard of care for adult patients with Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) and high risk of relapse. However, the stratification systems vary among study groups. Inadequate response at the level of minimal residual disease is the most commonly accepted factor indicating the need for alloHSCT. In this consensus paper on behalf of the European Working Group for Adult Acute Lymphoblastic Leukemia and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, we summarize available evidence and reflect current clinical practice in major European study groups regarding both indications for HSCT and particular aspects of the procedure including the choice of donor, source of stem cells and conditioning. Finally, we propose recommendations for daily clinical practice as well as for planning of prospective trials.

PMID: 30385870 [PubMed - as supplied by publisher]

Evaluation of effect of preoperative chemotherapy on Wilms' tumor histopathology.

To, 01/11/2018 - 21:12
Related Articles

Evaluation of effect of preoperative chemotherapy on Wilms' tumor histopathology.

J Pediatr Surg. 2018 Aug;53(8):1611-1614

Authors: Taskinen S, Lohi J, Koskenvuo M, Taskinen M

Abstract
PURPOSE: To evaluate usefulness of cutting needle biopsy (CNB) to recognize pediatric renal tumors and to predict the evolution of histology during preoperative chemotherapy of Wilms tumors.
METHODS: Ninety pediatric patients were operated for renal tumors at our institution in 1988-2015. We included all 64 patients who had undergone CNB at diagnosis and whose CNB and nephrectomy samples were available for re-evaluation.
RESULTS: The CNB was diagnostic in all 59 Wilms tumors but only in two out of five non-Wilms tumors. Anaplasia was missed by CNB in one of three with diffuse anaplasia in nephrectomy specimens. In Wilms tumors the proportions of the blastemal, stromal and epithelial components were 55% (IQR 25-85), 28% (IQR 10-58) and 2% (IQR 0-10) in CNB samples and 5% (IQR 0-64), 15% (IQR 0-50) and 15% (IQR 0-44) in the nephrectomy specimens (p-values 0.002, 0.599 and 0.005 respectively). The degree of tumor necrosis was in median 80% (IQR 21-97), after preoperative chemotherapy. The degree of tumor necrosis after chemotherapy had a positive correlation with the proportion of blastemal component (p=0.008) and a negative correlation with proportion of epithelial component in pre-chemotherapy CNB samples (p<0.001).
CONCLUSIONS: Wilms tumors are usually recognizable unlike non-Wilms tumors in CNB at diagnosis. In Wilms tumors, high blastemal cell content is associated with significant tumor necrosis during pre-operative chemotherapy. Our results do not support routine use of CNB in diagnosis of renal tumors.
TYPE OF STUDY: Retrospective review.
LEVEL OF EVIDENCE: Level III.

PMID: 29074135 [PubMed - indexed for MEDLINE]

Measuring childhood cancer late effects: evidence of a healthy survivor effect.

Ke, 31/10/2018 - 21:12
Related Articles

Measuring childhood cancer late effects: evidence of a healthy survivor effect.

Eur J Epidemiol. 2017 12;32(12):1089-1096

Authors: Asdahl PH, Ojha RP, Winther JF, Holmqvist AS, de Fine Licht S, Gudmundsdottir T, Madanat-Harjuoja L, Tryggvadottir L, Andersen KK, Hasle H, ALiCCS study group

Abstract
INTRODUCTION: Given considerable focus on health outcomes among childhood cancer survivors, we aimed to explore whether survivor bias is apparent during long-term follow-up of childhood cancer survivors.
METHODS: We identified all 1-year survivors of cancer diagnosed before 20 years of age in Denmark, Finland, Iceland, and Sweden. From the general population, we randomly sampled a comparison cohort. Study individuals were followed for hospitalizations for diseases of the gastroenterological tract, endocrine system, cardiovascular system, or urinary tract from the start of the cancer registries to 2010. We estimated cumulative incidence with death as competing risk and used threshold regression to compare the hazards of the diseases of interest at ages 20, 40, 60, and 75 years.
RESULTS: Our study included 27,007 one-year survivors of childhood cancer and 165,620 individuals from the general population. The cumulative incidence of all four outcomes was higher for childhood cancer survivors during early adulthood, but for three outcomes, the cumulative incidence was higher for the general population after age 55 years. The hazard ratios (HRs) decreased for all outcomes with increasing age, and for two of the outcomes, the hazards were higher for the general population at older ages (endocrine diseases: age-specific HRs = 3.0, 1.4, 1.0, 0.87; Cardiovascular diseases: age-specific HRs = 4.1, 1.4, 0.97, 0.84).
CONCLUSIONS: Our findings provide empirical evidence that survivor bias attenuates measures of association when comparing survivors with the general population. The design and analysis of studies among childhood cancer survivors, particularly as this population attains older ages, should account for survivor bias to avoid misinterpreting estimates of disease burden.

PMID: 29185125 [PubMed - indexed for MEDLINE]

Trends in patient outcome over the past two decades following allogeneic stem cell transplantation for acute myeloid leukemia. An ALWP/EBMT analysis.

Ti, 30/10/2018 - 21:11
Related Articles

Trends in patient outcome over the past two decades following allogeneic stem cell transplantation for acute myeloid leukemia. An ALWP/EBMT analysis.

J Intern Med. 2018 Oct 29;:

Authors: Canaani J, Beohou E, Labopin M, Ghavamzadeh A, Beelen D, Hamladji RM, Niederwieser D, Volin L, Markiewicz M, Arnold R, Mufti G, Ehninger G, Socié G, Kröger N, Mohty M, Nagler A

Abstract
BACKGROUND: Outcomes for patients with acute myeloid leukemia (AML) undergoing allogeneic stem cell transplantation (allo-SCT) have significantly improved in recent years.
OBJECTIVES: To assess the incremental improvement of transplanted AML patients in the last two decades.
METHODS: Patients included in this analysis were adult AML patients who underwent allo-SCT from an HLA matched sibling donor (MSD) or matched unrelated donor (MUD) in first remission. Patient outcomes were assessed between three cohorts according to the year of transplant (1993-2002, 2003-2007, and 2008-2012).
RESULTS: The analysis comprised a total of 20187 patients of whom 4763 were transplanted between 1993-2002, 5835 in 2003-2007, and 9589 in 2008-2012. In multivariate analysis, leukemia free survival (LFS) rates were significantly improved in more recently transplanted patients compared to patients transplanted in 1993-2002 [Hazard ratio (HR)=0.84, confidence interval (CI) 95%, 0.77-0.92; P=0.003], a benefit which also extended to improved overall survival (OS) (HR=0.8, CI 95%, 0.73-0.89; P<0.0001), and decreased non-relapse mortality (NRM) rates (HR=0.65, CI 95%, 0.56-0.75; P<0.0001). Subset analysis revealed that in MSD, the rates of LFS, NRM, and OS significantly improved in patients in the more recent cohort with similar results also seen in MUD. Finally, the incidence of acute graft versus host disease (GVHD) was significantly reduced leading to improved GVHD-free/relapse-free survival (GRFS) rates in more recently transplanted patients.
CONCLUSION: Outcome of allo-SCT for AML patients has markedly improved in the last two decades owing to decreased non-relapse mortality and improved rates of leukemia-free survival resulting in significantly longer survival. This article is protected by copyright. All rights reserved.

PMID: 30372796 [PubMed - as supplied by publisher]

Repression of Mcl-1 expression by the CDC7/CDK9 inhibitor PHA-767491 overcomes bone marrow stroma-mediated drug resistance in AML.

La, 27/10/2018 - 22:10
Related Articles

Repression of Mcl-1 expression by the CDC7/CDK9 inhibitor PHA-767491 overcomes bone marrow stroma-mediated drug resistance in AML.

Sci Rep. 2018 Oct 25;8(1):15752

Authors: O' Reilly E, Dhami SPS, Baev DV, Ortutay C, Halpin-McCormick A, Morrell R, Santocanale C, Samali A, Quinn J, O'Dwyer ME, Szegezdi E

Abstract
Acute myeloid leukaemia (AML) is an aggressive cancer with 50-75% of patients relapsing even after successful chemotherapy. The role of the bone marrow microenvironment (BMM) in protecting AML cells from chemotherapeutics and causing consequent relapse is increasingly recognised. However the role that the anti-apoptotic Bcl-2 proteins play as effectors of BMM-mediated drug resistance are less understood. Here we show that bone marrow mesenchymal stromal cells (BMSC) provide resistance to AML cells against BH3-mimetics, cytarabine and daunorubicin, but this is not mediated by Bcl-2 and/or Bcl-XL as previously thought. Instead, BMSCs induced Mcl-1 expression over Bcl-2 and/or Bcl-XL in AML cells and inhibition of Mcl-1 with a small-molecule inhibitor, A1210477, or repressing its expression with the CDC7/CDK9 dual-inhibitor, PHA-767491 restored sensitivity to BH3-mimetics. Furthermore, combined inhibition of Bcl-2/Bcl-XL and Mcl-1 could revert BMSC-mediated resistance against cytarabine + daunorubicin. Importantly, the CD34+/CD38- leukemic stem cell-encompassing population was equally sensitive to the combination of PHA-767491 and ABT-737. These results indicate that Bcl-2/Bcl-XL and Mcl-1 act in a redundant fashion as effectors of BMM-mediated AML drug resistance and highlight the potential of Mcl-1-repression to revert BMM-mediated drug resistance in the leukemic stem cell population, thus, prevent disease relapse and ultimately improve patient survival.

PMID: 30361682 [PubMed - in process]

Clinical and morphological practices in the diagnosis of transplant-associated microangiopathy: a study on behalf of Transplant Complications Working Party of the EBMT.

La, 27/10/2018 - 22:10
Related Articles

Clinical and morphological practices in the diagnosis of transplant-associated microangiopathy: a study on behalf of Transplant Complications Working Party of the EBMT.

Bone Marrow Transplant. 2018 Oct 25;:

Authors: Moiseev IS, Tsvetkova T, Aljurf M, Alnounou RM, Bogardt J, Chalandon Y, Drokov MY, Dvirnyk V, Faraci M, Friis LS, Giglio F, Greinix HT, Kornblit BT, Koelper C, Koenecke C, Lewandowski K, Niederwieser D, Passweg JR, Peczynski C, Penack O, Peric Z, Piekarska A, Ronchi PE, Rovo A, Rzepecki P, Scuderi F, Sigrist D, Siitonen SM, Stoelzel F, Sulek K, Tsakiris DA, Wilkowojska U, Duarte RF, Ruutu T, Basak GW

Abstract
Transplant-associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT). This study evaluated clinical and morphological practices of TA-TMA diagnosis in EBMT centers. Two questionnaires, one for transplant physician and one for morphologist, and also a set of electronic blood slides from 10 patients with TA-TMA and 10 control patients with various erythrocyte abnormalities, were implemented for evaluation. Seventeen EBMT centers participated in the study. Regarding criteria used for TA-TMA diagnosis, centers reported as follows: 41% of centers used the International Working Group (IWG) criteria, 41% used "overall TA-TMA" criteria and 18% used physician's decision. The threshold of schistocytes to establish TA-TMA diagnosis in the participating centers was significantly associated with morphological results of test cases evaluations (p = 0.002). The mean number of schistocytes reported from blood slide analyses were 4.3 ± 4.5% for TA-TMA cases (range 0-19.6%, coefficient of variation (CV) 0.7) and 1.3 ± 1.6% for control cases (range 0-8.3%, CV 0.8). Half of the centers reported schistocyte levels below 4% for 7/10 TA-TMA cases. The intracenter variability was low, indicating differences in the institutional practices of morphological evaluation. In conclusion, the survey identified the need for the standardization of TA-TMA morphological diagnosis.

PMID: 30361500 [PubMed - as supplied by publisher]

Dual cholinergic signals regulate daily migration of hematopoietic stem cells and leukocytes.

La, 27/10/2018 - 22:10
Related Articles

Dual cholinergic signals regulate daily migration of hematopoietic stem cells and leukocytes.

Blood. 2018 Oct 25;:

Authors: García-García A, Korn C, García-Fernández M, Domingues O, Villadiego J, Martín-Perez D, Isern J, Bejarano-García JA, Zimmer J, Pérez-Simón JA, Toledo-Aral JJ, Michel T, Airaksinen MS, Méndez-Ferrer S

Abstract
Hematopoietic stem and progenitor cells (HSPCs) and leukocytes circulate between the bone marrow (BM) and peripheral blood following circadian oscillations. Autonomic sympathetic noradrenergic signals have been shown to regulate HSPC and leukocyte trafficking, but the role of the cholinergic branch has remained unexplored. We have investigated the role of the cholinergic nervous system in the regulation of day/night traffic of HSPCs and leukocytes in mice. We show here that the autonomic cholinergic nervous system (including parasympathetic and sympathetic) dually regulates daily migration of HSPCs and leukocytes. At night, central parasympathetic cholinergic signals dampen sympathetic noradrenergic tone and decrease BM egress of HSPCs and leukocytes. However, at daytime, de-repressed sympathetic noradrenergic activity causes predominant BM egress of HSPCs and leukocytes via β3-AR. This egress is locally supported by light-triggered sympathetic cholinergic activity, which inhibits BM vascular cell adhesion and homing. In summary, central (parasympathetic) and local (sympathetic) cholinergic signals regulate day/night oscillations of circulating HSPCs and leukocytes. This study shows how both branches of the autonomic nervous system cooperate to orchestrate daily traffic of HSPCs and leukocytes.

PMID: 30361261 [PubMed - as supplied by publisher]

Smoking is Associated to DNA Methylation in Atherosclerotic Carotid Lesions.

Pe, 26/10/2018 - 22:10
Related Articles

Smoking is Associated to DNA Methylation in Atherosclerotic Carotid Lesions.

Circ Genom Precis Med. 2018 Sep;11(9):e002030

Authors: Siemelink MA, van der Laan SW, Haitjema S, van Koeverden ID, Schaap J, Wesseling M, de Jager SCA, Mokry M, van Iterson M, Dekkers KF, Luijk R, Foroughi Asl H, Michoel T, Björkegren JLM, Aavik E, Ylä-Herttuala S, de Borst GJ, Asselbergs FW, El Azzouzi H, den Ruijter HM, Heijmans BT, Pasterkamp G

Abstract
BACKGROUND: Tobacco smoking is a major risk factor for atherosclerotic disease and has been associated with DNA methylation (DNAm) changes in blood cells. However, whether smoking influences DNAm in the diseased vascular wall is unknown but may prove crucial in understanding the pathophysiology of atherosclerosis. In this study, we associated current tobacco smoking to epigenome-wide DNAm in atherosclerotic plaques from patients undergoing carotid endarterectomy.
METHODS: DNAm at commonly methylated sites (cytosine-guanine nucleotide pairs separated by a phospho-group [CpGs]) was assessed in atherosclerotic plaque samples and peripheral blood samples from 485 carotid endarterectomy patients. We tested the association of current tobacco smoking with DNAm corrected for age and sex. To control for bias and inflation because of cellular heterogeneity, we applied a Bayesian method to estimate an empirical null distribution as implemented by the R package bacon. Replication of the smoking-associated methylated CpGs in atherosclerotic plaques was executed in the second sample of 190 carotid endarterectomy patients, and results were meta-analyzed using a fixed-effects model.
RESULTS: Tobacco smoking was significantly associated to differential DNAm in atherosclerotic lesions of 4 CpGs (false discovery rate <0.05) mapped to 2 different genes ( AHRR, ITPK1) and 17 CpGs mapped to 8 genes and RNAs in blood. The strongest associations were found for CpGs mapped to the gene AHRR, a repressor of the aryl hydrocarbon receptor transcription factor involved in xenobiotic detoxification. One of these methylated CpGs were found to be regulated by local genetic variation.
CONCLUSIONS: The risk factor tobacco smoking associates with DNAm at multiple loci in carotid atherosclerotic lesions. These observations support further investigation of the relationship between risk factors and epigenetic regulation in atherosclerotic disease.

PMID: 30354327 [PubMed - in process]

ACTN1 mutations lead to a benign form of platelet macrocytosis not always associated with thrombocytopenia.

Ke, 24/10/2018 - 22:10
Related Articles

ACTN1 mutations lead to a benign form of platelet macrocytosis not always associated with thrombocytopenia.

Br J Haematol. 2018 Oct 23;:

Authors: Faleschini M, Melazzini F, Marconi C, Giangregorio T, Pippucci T, Cigalini E, Pecci A, Bottega R, Ramenghi U, Siitonen T, Seri M, Pastore A, Savoia A, Noris P

Abstract
The inherited thrombocytopenias (IT) are a heterogeneous group of diseases resulting from mutations in more than 30 different genes. Among them, ACTN1-related thrombocytopenia (ACTN1-RT; Online Mendelian Inheritance in Man: 615193) is one of the most recently identified forms. It has been described as a mild autosomal dominant macrothrombocytopenia caused by mutations in ACTN1, a gene encoding for one of the two non-muscle isoforms of α-actinin. We recently identified seven new unrelated families with ACTN1-RT caused by different mutations. Two of them are novel missense variants (p.Trp128Cys and p.Pro233Leu), whose pathogenic role has been confirmed by in vitro studies. Together with the 10 families we have previously described, our cohort of ACTN1-RT now consists of 49 individuals carrying ACTN1 mutations. This is the largest case series ever collected and enabled a critical evaluation of the clinical aspects of the disease. We concluded that ACTN1-RT is the fourth most frequent form of IT worldwide and it is characterized by platelet macrocytosis in all affected subjects and mild thrombocytopenia in less than 80% of cases. The risk of bleeding, either spontaneous or upon haemostatic challenge, is negligible and there are no other associated defects, either congenital or acquired. Therefore, ACTN1-RT is a benign form of IT, whose diagnosis provides affected individuals and their families with a good prognosis.

PMID: 30351444 [PubMed - as supplied by publisher]

Ex vivo and in vivo T cell-depleted allogeneic stem cell transplantation in patients with acute myeloid leukemia in first complete remission resulted in similar overall survival: on behalf of the ALWP of the EBMT and the MSKCC.

Ma, 22/10/2018 - 22:10
Related Articles

Ex vivo and in vivo T cell-depleted allogeneic stem cell transplantation in patients with acute myeloid leukemia in first complete remission resulted in similar overall survival: on behalf of the ALWP of the EBMT and the MSKCC.

J Hematol Oncol. 2018 Oct 20;11(1):127

Authors: Malard F, Labopin M, Cho C, Blaise D, Papadopoulos EB, Passweg J, O'Reilly R, Forcade E, Maloy M, Volin L, Castro-Malaspina H, Hicheri Y, Jakubowski AA, Orvain C, Giralt S, Mohty M, Nagler A, Perales MA

Abstract
BACKGROUND: Graft-versus-host disease (GVHD) is one of the leading causes of non-relapse mortality and morbidity after allogeneic hematopoietic stem cell transplantation (allo-HCT).
METHODS: We evaluated the outcomes of two well-established strategies used for GVHD prevention: in vivo T cell depletion using antithymocyte globulin (ATG) and ex vivo T cell depletion using a CD34-selected (CD34+) graft. A total of 525 adult patients (363 ATG, 162 CD34+) with intermediate or high-risk cytogenetics acute myeloid leukemia (AML) in first complete remission (CR1) were included. Patients underwent myeloablative allo-HCT using matched related or unrelated donors.
RESULTS: Two-year overall survival estimate was 69.9% (95% CI, 58.5-69.4) in the ATG group and 67.6% (95% CI, 60.3-74.9) in the CD34+ group (p = 0.31). The cumulative incidence of grade II-IV acute GVHD and chronic GVHD was higher in the ATG cohort [HR 2.0 (95% CI 1.1-3.7), p = 0.02; HR 15.1 (95% CI 5.3-42.2), p < 0.0001]. Parameters associated with a lower GVHD-free relapse-free survival (GRFS) were ATG [HR 1.6 (95% CI 1.1-2.2), p = 0.006], adverse cytogenetic [HR 1.7 (95% CI 1.3-2.2), p = 0.0004], and the use of an unrelated donor [HR 1.4 (95% CI 1.0-1.9), p = 0.02]. There were no statistical differences between ATG and CD34+ in terms of relapse [HR 1.52 (95% CI 0.96-2.42), p = 0.07], non-relapse mortality [HR 0.96 (95% CI 0.54-1.74), p = 0.90], overall survival [HR 1.43 (95% CI 0.97-2.11), p = 0.07], and leukemia-free survival [HR 1.25 (95% CI 0.88-1.78), p = 0.21]. Significantly, more deaths related to infection occurred in the CD34+ group (16/52 vs. 19/112, p = 0.04).
CONCLUSIONS: These data suggest that both ex vivo CD34-selected and in vivo ATG T cell depletion are associated with a rather high OS and should be compared in a prospective randomized trial.

PMID: 30342553 [PubMed - in process]

Sweden and Finland need to improve the support provided for the siblings of children with cancer.

Ke, 17/10/2018 - 22:09
Related Articles

Sweden and Finland need to improve the support provided for the siblings of children with cancer.

Acta Paediatr. 2018 Oct 16;:

Authors: Lövgren M, Mogensen N, Harila-Saari A, Lähteenmäki PM, Kreicbergs U

Abstract
Evidence favours sibling support as a standard of care in paediatric oncology (1). Guidelines published in 1999 by the International Society of Paediatric Oncology (2) recommended involving siblings in the ill child's care and supporting siblings during and after the illness. Studies have shown that this is something that siblings want and need (3) and lack of support has increased the risk of long-term psychological distress (4). Sibling support varies between countries. This article is protected by copyright. All rights reserved.

PMID: 30325536 [PubMed - as supplied by publisher]

Methotrexate polyglutamate levels and co-distributions in childhood acute lymphoblastic leukemia maintenance therapy.

Ke, 17/10/2018 - 22:09
Related Articles

Methotrexate polyglutamate levels and co-distributions in childhood acute lymphoblastic leukemia maintenance therapy.

Cancer Chemother Pharmacol. 2018 Oct 15;:

Authors: Nersting J, Nielsen SN, Grell K, Paerregaard M, Abrahamsson J, Lund B, Jonsson OG, Pruunsild K, Vaitkeviciene G, Kanerva J, Schmiegelow K, Nordic Society of Paediatric Haematology and Oncology (NOPHO)

Abstract
PURPOSE: Methotrexate polyglutamates (MTXpg) facilitate incorporation of thioguanine nucleotides into DNA (DNA-TG, the primary cytotoxic thiopurine metabolite and outcome determinant in MTX/6-mercaptopurine treatment of childhood ALL). We hypothesized that mapping erythrocyte levels of MTXpg with 1-6 glutamates and their associations with DNA-TG formation would facilitate future guidelines for maintenance therapy dosing.
METHODS AND RESULTS: Summed MTX with 1-6 glutamates resolved by LCMS [median (interquartile): 5.47 (3.58-7.69) nmol/mmol hemoglobin] was in agreement with total MTX by radio ligand assay. In 16,389 blood samples from 1426 ALL maintenance therapy patients, MTXpg3 21.0 (15.2-27.4)% was the predominant metabolite, and MTXpg1 (the maternal drug) constituted 38.6 (27.2-50.2)% of MTXpg1-6. All subsets correlated; the strongest associations were between metabolites with similar polyglutamate lengths. Correlations of MTXpg1 with MTXpg2 and MTXpg3,4,5,6 were rs = 0.68 and rs = 0.25-0.42, respectively. Intercorrelations of MTXpg3,4,5,6 were all rs ≥ 0.51. MTXpg4 accounted for 29.8 (24.7-33.3)% of MTXpg3-6, yet explained 96% of the summed MTXpg3-6 variation. MTXpg1-4, MTXpg1-6, MTXpg2-6 and MTXpg3 were all associated with DNA-TG levels (p < 0.00001), but collinearity precluded identification of the most informative subset.
CONCLUSIONS: Measuring erythrocyte MTXpg4 simplifies and can replace longer chain MTXpg monitoring. Resolving individual MTXpg identifies samples that are unsuitable for dose guidance due to high levels of MTXpg1 remaining in the plasma fraction because of recent MTX intake. All tested MTXpg subsets correlated with DNA-TG and may be used for ALL maintenance therapy dose adjustments, but the most informative subset remains to be identified.

PMID: 30324220 [PubMed - as supplied by publisher]