Erythropoiesis-stimulating agents significantly delay the onset of a regular transfusion need in nontransfused patients with lower-risk myelodysplastic syndrome

Background The EUMDS registry is an unique prospective, longitudinal observational registry enrolling newly diagnosed patients with lower‐risk myelodysplastic syndrome (MDS) from 17 European countries from both university hospitals and smaller regional hospitals. Objective The aim of this study was to describe the usage and clinical impact of erythropoiesis‐stimulating agents (ESAs) in 1696 patients enrolled between 2008 and 2014. Methods The effects of ESAs on outcomes were assessed using proportional hazards models weighting observations by propensity to receive ESA treatment within a subset of anaemic patients with or without a regular transfusion need. Results ESA treatment (median duration of 27.5 months, range 0–77 months) was administered to 773 patients (45.6%). Outcomes were assessed in 897 patients (484 ESA treated and 413 untreated). ESA treatment was associated with a nonsignificant survival benefit (HR 0.82, 95% CI: 0.65–1.04, P = 0.09); this benefit was larger amongst patients without prior transfusions (P = 0.07). Amongst 539 patients for whom response to ESA treatment could be defined, median time to first post‐ESA treatment transfusion was 6.1 months (IQR: 4.3–15.9 months) in those transfused before ESA treatment compared to 23.3 months (IQR: 7.0–47.8 months) in patients without prior transfusions (HR 2.4, 95% CI: 1.7–3.3, P < 0.0001). Responding patients had a better prognosis in terms of a lower risk of death (HR 0.65, 95% CI: 0.45–0.893, P = 0.018), whereas there was no significant effect on the risk of progression to acute myeloid leukaemia (HR 0.71, 95% CI: 0.39–1.29, P = 0.27). Conclusion Appropriate use of ESAs can significantly delay the onset of a regular transfusion need in patients with lower‐risk MDS

Adult-Onset Ataxia with Neuropathy and White Matter Abnormalities Due to a Novel SAMD9L Variant

Variants in tumor suppressor genes and in genes encoding DNA repairing proteins are associated with syndromes conferring neurologic features and increased risk for malignancy. The best example for these conditions is ataxia-telangiectasia (AT). A more rare and recent disease is an ataxia-pancytopenia syndrome (ATXPC) associated with heterozygous gain-of-function variants in the tumor suppressor gene SAMD9L (MIM 159550). Here, we describe a patient with a complex cerebellar syndrome associated with a novel SAMD9L pathogenic variant.publishedVersio

Laxens nedströmsvandring mot fiskavledare till Stornorrfors fisktrappa i Umeälvens nedre del

Rapporten sammanfattar våra arbeten med målsättning att skapa en fungerande fiskavledning för nedströmsvandrande fisk i vid Stornorrfors kraftverkskomplex i Umeälven. Rapporten visar även på verksamheter som nyttjats vid planering och utvärdering av gjorda åtgärder. Åtgärder i fisktrappan, fiskavledare och utrustning för registrering av PIT-tags har möjliggjorts genom finansiering av Europeiska Fiskefonden, Havs- och Vattenmyndigheten, Umeå kommun, Vattenfall och SLU. Arbetena har genomförts som två pilotprojekt (3b Nedströmsvandring Stornorrfors 2009-2010 och 3b2 Nedströmsvandring Stornorrfors 2011-2013). Vilda lax- och öring bestånd i våra älvar är viktiga naturresurser för människan och ekosystemet. Vindelälvens naturliga fiskproduktion av lax- och havsöring ungar är betydande för Östersjöns laxbestånd. De senaste åren har mer än 10 000 lax årligen vandrat uppströms för lek i älven. Många föräldrafiskar (Kelt, vraklax, besa, mm) överlever leken och vill vandra tillbaka till havet. Laxens naturliga avkomma, smolten, strävar också att ta sig till födoområdena i Östersjön. I flödesreglerade vattendrag som Umeälven med sitt unika laxbestånd i biflödet Vindelälven finns problem med dödlighet då kelt och smolt på sin nedströmsvandring ska passera Stornorrfors kraftverk. I Umeälvens nedre del färdigställdes en ny fisktrappa i Norrfors 2010 som utrustats med en ”fiskavledare”. Projektets mål var att bygga och ansluta fiskavledaren till nya fisktrappan och utvärdera dess funktion/effektivitet. Det mätbara målet för den planerade anläggningen vid Stornorrfors utskovsdamm sattes till att 75 % av den utvandrande vilda smolten och minst 50 % av den övervintrande kelten skulle avledas till nya fisktrappan för vidare vandring till havet. Detta mål kunde inte uppnås. Den nya fisktrappan skulle alltså fungera som ett klassiskt "omlöp" förbi kraftverket. Vild smolt har märkts med Passiva Integrerade Transpondrar (PIT) eller aktiva Radiomärken (RT) och senare skannats vid passage i fisktrappsområdet (PIT + RT-märkt fisk) eller vid intaget till Stornorrfors kraftverk (RT-märkt fisk). SLU’s utvärdering av ledarmens funktion och fiskens vandring nedströms har visat att fiskavledarens funktion varit mycket svår att kontrollera då ledarmen inte fungerat som tänkt i den tuffa strömmiljön ovan fisktrappans område mellan 2010-2012. Avledningseffektiviteten kunde med visst förtroende endast värderas vid 2013 års försök med PIT-märkt fisk (n=1749 fiskar) som släpptes dagligen efter fångst i Vindelälven (INDEX Spöland) när flödet var < 800 m3/s i älven. Den totala avledningseffektiviteten visade sig vara 4,5 %. Begränsande för utvärderingen har varit att stora grupper smolt periodvis inte kunnat fångas och märkas på grund av höga flöden i Vindelälven. Effektiviteten i ledarmen har varierat mellan 0 och 100 % under säsongen. Väldigt få Kelt av lax kunde avledas. Höga turbinflöden tycks haft en positiv inverkan på ledarmens funktion. Smoltens passage nedströms i och genom fisktrappan verkar fungera utan större problem. Via PIT-märkt fisk och videofilmning i flera delförsök kunde vi visa på en lyckad genomfart där laxsmolten passerar fisktrappan inom några timmar till 2-3 dagar. Flödesmätning och modellering av strömningen runt fiskavledarens område mot ingången till nya fisktrappan visar att ledarmen borde ökas till ca 150 meters längd istället för dagens 110 meter. Flödesmodelleringar visar då att en större del av ytströmmen kan styras in mot fisktrappans ingång. Försöken med fångst, märkning, utsättning och återfångst har fungerat bra och PIT-märkningstekniken bedöms överlägsen andra märktekniker för detektering av fisk om detekteringsutrustning installerats. Detta kan utvecklas vidare inom ramen för indexälvsverksamheten (ICES-DCF) som nu bedrivs i Vindelälven. Sverige bör fortsätta att ta ansvar för den här typen av utveckling då det finns samordningsvinster mellan indexvattendrag, fiskavledning och utvärdering av fisktrappan för lekvandrande fisk. Lyckas man avleda den naturligt producerade avkomman av lax och öring i reglerade vattendrag med unika bestånd finns mycket att vinna för att etablera långsiktigt hållbara bestånd av vandringsfisk. Den typ av fiskavledare som nu prövats har tidigare inte prövats i Europa varför detta pilotprojekt är unikt. Arbetet som nu avslutats har varit ett samverkansprojekt mellan Europeiska Fiskerifonden, Havs- och Vattenmyndigheten, vattenkraftsägare, lokala och nationella fiskeriadministratörer samt forskare i fiskbiologi och hydraulik

The effects of continued azacitidine treatment cycles on response in higher risk patients with myelodysplastic syndromes: an update

The international, phase III, multi-centre AZA-001 trial demonstrated azacitidine (AZA) is the first treatment to significantly extend overall survival (OS) in higher risk myelodysplastic syndromes (MDS) patients (Fenaux (2007) Blood 110 817). The current treatment paradigm, which is based on a relationship between complete remission (CR) and survival, is increasingly being questioned (Cheson (2006) Blood 108 419). Results of AZA-001 show CR is sufficient but not necessary to prolong OS (List (2008) Clin Oncol 26 7006). Indeed, the AZA CR rate in AZA-001 was modest (17%), while partial remission (PR, 12%) and haematological improvement (HI, 49%) were also predictive of prolonged survival. This analysis was conducted to assess the median number of AZA treatment cycles associated with achievement of first response, as measured by IWG 2000-defined CR, PR or HI (major + minor). The number of treatment cycles from first response to best response was also measured

Haploinsufficiency of RPS14 in 5q− syndrome is associated with deregulation of ribosomal- and translation-related genes

We have previously demonstrated haploinsufficiency of the ribosomal gene RPS14, which is required for the maturation of 40S ribosomal subunits and maps to the commonly deleted region, in the 5q− syndrome. Patients with Diamond-Blackfan anaemia (DBA) show haploinsufficiency of the closely related ribosomal protein RPS19, and show a consequent downregulation of multiple ribosomal- and translation-related genes. By analogy with DBA, we have investigated the expression profiles of a large group of ribosomal- and translation-related genes in the CD34+ cells of 15 myelodysplastic syndrome (MDS) patients with 5q− syndrome, 18 MDS patients with refractory anaemia (RA) and a normal karyotype, and 17 healthy controls. In this three-way comparison, 55 of 579 ribosomal- and translation-related probe sets were found to be significantly differentially expressed, with approximately 90% of these showing lower expression levels in the 5q− syndrome patient group. Using hierarchical clustering, patients with the 5q− syndrome could be separated both from other patients with RA and healthy controls solely on the basis of the deregulated expression of ribosomal- and translation-related genes. Patients with the 5q− syndrome have a defect in the expression of genes involved in ribosome biogenesis and in the control of translation, suggesting that the 5q− syndrome represents a disorder of aberrant ribosome biogenesis

Azacitidine prolongs overall survival and reduces infections and hospitalizations in patients with WHO-defined acute myeloid leukaemia compared with conventional care regimens: an update

Azacitidine (AZA), as demonstrated in the phase III trial (AZA-001), is the first MDS treatment to significantly prolong overall survival (OS) in higher risk MDS pts ((2007) Blood 110 817). Approximately, one-third of the patients (pts) enrolled in AZA-001 were FAB RAEB-T (≥20–30% blasts) and now meet the WHO criteria for acute myeloid leukaemia (AML) ((1999) Blood 17 3835). Considering the poor prognosis (median survival <1 year) and the poor response to chemotherapy in these pts, this sub-group analysis evaluated the effects of AZA versus conventional care regimens (CCR) on OS and on response rates in pts with WHO AML

The Role of the Iron Transporter ABCB7 in Refractory Anemia with Ring Sideroblasts

Refractory Anemia with Ring Sideroblasts (RARS) is an acquired myelodysplastic syndrome (MDS) characterized by an excess iron accumulation in the mitochondria of erythroblasts. The pathogenesis of RARS and the cause of this unusual pattern of iron deposition remain unknown. We considered that the inherited X-linked sideroblastic anemia with ataxia (XLSA/A) might be informative for the acquired disorder, RARS. XLSA/A is caused by partial inactivating mutations of the ABCB7 ATP-binding cassette transporter gene, which functions to enable transport of iron from the mitochondria to the cytoplasm. Furthermore, ABCB7 gene silencing in HeLa cells causes an accumulation of iron in the mitochondria. We have studied the role of ABCB7 in RARS by DNA sequencing, methylation studies, and gene expression studies in primary CD34+ cells and in cultured erythroblasts. The DNA sequence of the ABCB7 gene is normal in patients with RARS. We have investigated ABCB7 gene expression levels in the CD34+ cells of 122 MDS cases, comprising 35 patients with refractory anemia (RA), 33 patients with RARS and 54 patients with RA with excess blasts (RAEB), and in the CD34+ cells of 16 healthy controls. We found that the expression levels of ABCB7 are significantly lower in the RARS group. RARS is thus characterized by lower levels of ABCB7 gene expression in comparison to other MDS subtypes. Moreover, we find a strong relationship between increasing percentage of bone marrow ring sideroblasts and decreasing ABCB7 gene expression levels. Erythroblast cell cultures confirm the low levels of ABCB7 gene expression levels in RARS. These data provide an important link between inherited and acquired forms of sideroblastic anemia and indicate that ABCB7 is a strong candidate gene for RARS

Limited clinical efficacy of azacitidine in transfusion-dependent, growth factor-resistant, low- and Int-1-risk MDS:Results from the nordic NMDSG08A phase II trial

This prospective phase II study evaluated the efficacy of azacitidine (Aza) + erythropoietin (Epo) in transfusion-dependent patients with lower-risk myelodysplastic syndrome (MDS). Patients ineligible for or refractory to full-dose Epo + granulocyte colony stimulation factors for 48 weeks and a transfusion need of ≥ 4 units over 8 weeks were included. Aza 75mgm -2 d-1, 5/28 days, was given for six cycles; non-responding patients received another three cycles combined with Epo 60 000 units per week. Primary end point was transfusion independence (TI). All patients underwent targeted mutational screen for 42 candidate genes. Thirty enrolled patients received ≥ one cycle of Aza. Ten patients discontinued the study early, 7 due to adverse events including 2 deaths. Thirty-eight serious adverse events were reported, the most common being infection. Five patients achieved TI after six cycles and one after Aza + Epo, giving a total response rate of 20%. Mutational screening revealed a high frequency of recurrent mutations. Although no single mutation predicted for response, SF3A1 (n = 3) and DNMT3A (n = 4) were only observed in nonresponders. We conclude that Aza can induce TI in severely anemic MDS patients, but efficacy is limited, toxicity substantial and most responses of short duration. This treatment cannot be generally recommended in lower-risk MDS. Mutational screening revealed a high frequency of mutations

Somatic mutations in lymphocytes in patients with immune-mediated aplastic anemia

The prevalence and functional impact of somatic mutations in nonleukemic T cells is not well characterized, although clonal T-cell expansions are common. In immune-mediated aplastic anemia (AA), cytotoxic T-cell expansions are shown to participate in disease pathogenesis. We investigated the mutation profiles of T cells in AA by a custom panel of 2533 genes. We sequenced CD4+ and CD8+ T cells of 24 AA patients and compared the results to 20 healthy controls and whole-exome sequencing of 37 patients with AA. Somatic variants were common both in patients and healthy controls but enriched to AA patients' CD8+ T cells, which accumulated most mutations on JAK-STAT and MAPK pathways. Mutation burden was associated with CD8+ T-cell clonality, assessed by T-cell receptor beta sequencing. To understand the effect of mutations, we performed single-cell sequencing of AA patients carrying STAT3 or other mutations in CD8+ T cells. STAT3 mutated clone was cytotoxic, clearly distinguishable from other CD8+ T cells, and attenuated by successful immunosuppressive treatment. Our results suggest that somatic mutations in T cells are common, associate with clonality, and can alter T-cell phenotype, warranting further investigation of their role in the pathogenesis of AA.Peer reviewe