The Use of Thalidomide in Severe Refractory Anaemia Due to Gastric Antral Vascular Ectasia (GAVE) in Cirrhosis?

Gastric antral vascular ectasia (GAVE) is a rare cause of upper gastrointestinal bleeding associated with cirrhosis. The first-line treatment is endoscopic therapy with argon plasma coagulation (APC). There is a high recurrence rate, but some evidence suggests that thalidomide could play an important role in controlling refractory anaemia due to GAVE. The authors present the case of a cirrhotic patient with a recent diagnosis of GAVE, who underwent multiple endoscopic treatments and blood transfusions because of haematemesis. The patient started thalidomide and 6 months later, there was no recurrence of haematemesis and haemoglobin levels were stable, with no reported adverse effects.

A Severe Refractory Anaemia and Fever of Unknow Origin: Human Parvovirus B19 Reactivation

Reactivation of human parvovirus B19 is exceptional and characteristic of immunosuppression, with anaemia being the predominant manifestation although pancytopenia and thrombotic microangiopathy may also occur. We describe a patient with a history of diffuse large B-cell lymphoma with pure erythrocyte aplasia due to reactivation of parvovirus B19, who was treated with corticosteroids and immunoglobulins.

Fatal Case Of Solid Organ Infarcts In a Case Of Myelodysplastic Syndrome (MDS) With Refractory Anaemia

Myelodysplastic syndrome (MDS) usually presents with cytopenias because of bone marrow failure. Solid organ infarcts in myelodysplastic syndrome (MDS) is rarest complication. We report an elderly male, admitted with complaints of pain abdomen mainly in both flanks and swelling all over the body. Peripheral blood smear, bone marrow aspirate for cytology were suggestive of myelodysplastic syndrome(MDS) with refractory anaemia. Fluorescence in situ hybridization(FISH) were negative for any chromosomal abnormalities. His CECT abdomen was done which revealed hepatosplenomegaly with hyperdense liver with multiple splenic and renal infarcts and patient was treated as a case of MDS with refractory anaemia with solid organ infarcts. Over a period of 3 days, he had Acute Kidney Injury (AKI). Patient succumbed on fifth day.

Bone marrow dyspoiesis associated with severe refractory anaemia in liver cirrhosis

Background and aimPeripheral cytopaenias and dyspoiesis are common in cirrhosis; however, the prevalence of dyspoiesis and its contribution in cirrhosis-related cytopaenias has not been studied. We aimed to study the bone marrow (BM) dyspoiesis and its impact on peripheral blood cell counts and refractory anaemia in patients with cirrhosis.Patients and methodsWe reviewed all the BM aspirates and biopsies of cirrhotic cases, done from 2011 to 2018 for clinical indications. Dyspoiesis was considered if >5% of the precursor cells of any of the three lineages showed dyspoietic changes. Primary haematological or non-haematological malignancies, chronic kidney disease, drug intake, acute and chronic hepatitis and granulomatous disease were excluded.ResultsOf 608 these, 82 cases (13.5%) showed dyspoiesis in the BM precursors. There was no difference in age (p=0.16), gender (p=0.58) and spleen size (p=0.35) in cases with or without dyspoiesis. Majority of the cases had dyspoiesis in erythroid series (62, 75.6%) and megakaryocytes (15, 18.2%). Dyspoiesis was more prominent in alcoholics 44 cases (53.6%) and autoimmune diseases 13 cases (15.8%). Erythroid hyperplasia (47.7±14.4 vs 40±11.1; p<0.001) was more in cases with dyserythropoiesis, indicating ineffective erythropoiesis. Patients with dyspoiesis had lower haemoglobin (7.5±1.9 vs 9.3±2.2 g/dL, p<0.001). 54 (8.07%) had refractory anaemia with dyspoiesis present in 48 (88.8%) (p<0.01). Dyspoiesis was independently associated with refractory anaemia when adjusted for age, gender, aetiology and liver disease severity.ConclusionsBM dyspoiesis, especially dyserythropoiesis, is associated with severe refractory anaemia in patients with cirrhosis and requires new therapeutic approaches.

Next Generation Sequencing and Microrna Assay in a Cohort of Patients Affected By Myelodysplastic Syndromes. an Analysis of Clinical and Genotypic Features

Introduction : The myelodysplastic syndromes (MDS) are a group of clonal haematopoietic stem cell disorders and they can be a consequence of genomic/chromosomal instability. The World Health Organization (WHO) 2008 classification divides the MDS in 4 types: refractory anaemia with excess of blast (RAEB), refractory anaemia (RA), refractory cytopenia with multilineage dysplasia (RCMD) and chronic myelomonocytic leukaemia (CMML). Various mechanisms contribute to the pathogenesis and prognosis of the disease and currently next generation sequencing (NGS) detects pathogenic gene mutations that can allocate patients to different risk classes. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression via post-transcriptional mechanisms and may have oncogenic properties or act as tumour suppressor and have an active role in the onset of myeloid disorders. A prospective study based on integration of NGS and miRNA quantification was launched at Policlinico San Martino in 2017. The aim of this paper is to report the results and the correlation with the clinical features. Patients and methods: 28 consecutive patients were enrolled in this study because they met our eligibility criteria: (i) availability of bone marrow sample at diagnosis, (ii) IPSS and (iii) clinical follow up. Specifically, 11 patients were affected by RAEB, 9 by RA, 5 by RCMD and 3 by CMML. Median age was 66 years old (48 - 85). Eight patients evolved into acute myeloid leukaemia. NGS analysis was performed with Myeloid Oncomine Panel Thermo fisher; miRNA expression was quantified with TaqMan Advanced miRNA Cards. In the context of a machine learning supervised analysis we evaluated if there were significant differences in the miRNAs expression among the patients classified based on the WHO 2008 classification. This analysis was conducted using l1l2-penalized regularization method within PALLADIO, a machine-learning framework that can provide robust variable selection in high-dimensional problems. The identified miRNA signature was characterized though a miRNA enrichment analysis using the webtoolkit WebGestalt. Results: each patient carried a distinctive miRNA signature composed by a median of 650 miRNA. The supervised analysis identified a signature of 24 miRNAs (table 1) able to discriminate the 4 WHO classes with a balanced accuracy of 0.616 (whose significance with respect to the balanced accuracy distribution of the permutation batch experiments has 2.206e-08 p-value). Among these miRNAs, 14 were selected because frequently up-regulated in most the patients of one or more WHO classes (figure 1). NGS identified mutations in 43% of patients affected by RAEB, RCMD and CMML in genes known to be pathogenic for MDS (figure 2). miRNA enrichment analysis allowed the identifications of genes involved in (i) pathways (some in common and some specific for a WHO class) likely involved in the onset of MDS, (ii) in diseases related to MDS and to disease evolution into acute myeloid leukaemia. Some of these genes were the same with the ones identified by NGS in our study population (i.e. TET2, ASLX1, RUNX1, IKZF1, SRSF2) but many others (e.g., GATA2, NfkB, BCL2, CD46, mTOR) were not detected by NGS but are likely to be involved in MDS pathogenesis and disease progression as described previously by other groups (figure 3). C onclusions : our study gives a further input toward the understanding of pathogenesis in MDS through the integration of miRNA analysis with NGS at the diagnosis of MDS. With the identification of specific miRNA signature for each patient it is possible to highlight multiple genes pathway that may contribute to the onset and progression of MDS. In a prospective trial we also aim to verify if a specific miRNA signature is linked to azacitidine resistance. Disclosures Mufti: Celgene: Consultancy, Research Funding.

Iron Support in Erythropoietin Treatment in Myelodysplastic Syndrome Patients Affected by Low-Risk Refractory Anaemia: Real-Life Evidence from an Italian Setting

Refractory anaemia (RA) among myelodysplastic syndrome (MDS) is associated with a partial functional iron deficit and may require transfusions. In low-risk lymphoma and solid tumour patients, iron support improves erythropoietin (EPO) cost-effectiveness in treating anaemia. The aim of this study is to see if oral sucrosomial iron support improves the cost-effectiveness of EPO treatment in MDS patients affected by low-risk RA. We treated patients with EPO only or with EPO plus oral sucrosomial iron or intravenous (i.v.) iron. The need for transfusions was lowest in the group taking oral iron (p = 0.016) or not receiving supplementation at all (p = 0.022). We compared costs of EPO with i.v. ferric gluconate or oral sucrosomial iron supplementation or no iron supplementation. The oral iron group had fewer side effects, fewer patient medical visits in the out-patient setting, and fewer transfusions; this led to higher savings on direct hospital costs and indirect patient costs (lost days at work) and translated into a 50% abatement of overall expenditures. EPO treatment-related expenditures in MDS-RA patients were lowest with oral sucrosomial iron supplementation (Sideral®), with a longer interval between EPO administration in maintenance treatment, quicker hemoglobin recovery, lower ferritin increase and fewer blood transfusions.

DNA repair gene expressions are related to bone marrow cellularity in myelodysplastic syndrome

ObjectiveTo evaluate the expression of genes related to nuclear excision (ERCC8, XPA and XPC), homologous recombination and non-homologous end-joining (ATM, BRCA1, BRCA2 and LIG4) repair mechanisms, using quantitative PCR methodologies, and it relation with bone marrow cellularity in myelodysplastic syndrome (MDS).Methods and resultsA total of 51 adult de novo patients with MDS (3 refractory anaemia (RA), 11 refractory anaemia with ringed sideroblasts (RARS), 28 refractory cytopenia with multilineage dysplasia (RCMD), 3 refractory anaemia with excess blasts type I (RAEB-I), 5 refractory anaemia with excess blasts type II (RAEB-II), and 1 chronic myelomonocytic leukaemia (CMML) were evaluated. For karyotype, 16.2% patients were defined as very low prognosis, 59.5% low risk, 8.1% intermediate risk, 5.4% high risk and 10.8% very high risk. For bone marrow cellularity, 17.6%, 17.6% and 64.7% presented as hypocellular, normocellular and hypercellular, respectively. Patients with hypocellular MDS had significantly decreased expression of ATM (p=0.000), BRCA1 (p=0.014), BRCA2 (p=0.003), LIG4 (p=0.004) and ERCC8 (p=0.000) than those with normocellular/hypercellular bone marrow, whereas XPA (p=0.049) and XPC (p=0.000) genes were increased. In patients with hypoplastic MDS, a low expression of ATM (p=0.0268), LIG4 (p=0.0199) and ERCC8 (p=0.0493) was significantly associated with the presence of chromosomal abnormalities. We detected positive correlations between BRCA1 and BRCA2 (r=0.416; p=0.007), ATM and LIG4 (r=0.472; p=0.001), LIG4 and BRCA1 (r=0.333; p=0.026), LIG4 and BRCA2 (r=0.334; p=0.025), ATM and XPA (r=0.377; p=0.008), ATM and XPC (r=0.287; p=0.046), LIG4 and XPC (r=0.371; p=0.007) and XPA and XPC genes (r=0.895; p=0.0000). We also found among all patients evaluated that correlation with LIG4 occurred most often.ConclusionsThese correlations demonstrate the important intrinsic relations between single and double DNA strand breaks genes in MDS, emphasising that these genes are related to MDS pathogenesis.

Multicentre, open-label, randomised, parallel-group, superiority study to compare the efficacy of octreotide therapy 40 mg monthly versus standard of care in patients with refractory anaemia due to gastrointestinal bleeding from small bowel angiodysplasias: a protocol of the OCEAN trial

IntroductionGastrointestinal angiodysplasias are an important cause of difficult-to-manage bleeding, especially in older patients. Endoscopic coagulation of angiodysplasias is the mainstay of treatment, but may be difficult for small bowel angiodysplasias because of the inability to reach them for endoscopic intervention. Some patients are red blood cell (RBC) transfusion dependent due to frequent rebleeding despite endoscopic treatment. In small cohort studies, octreotide appears to decrease the number of bleeding episodes in patients with RBC transfusion dependency due to gastrointestinal angiodysplasias. This trial will assess the efficacy of octreotide in decreasing the need for RBC transfusions and parenteral iron in patients with anaemia due to gastrointestinal bleeding of small bowel angiodysplasias despite endoscopic intervention.Study designRandomised controlled, superiority, open-label multicentre trial.Participants62 patients will be included with refractory anaemia due to small bowel angiodysplasias, who are RBC transfusion or iron infusion dependent despite endoscopic intervention and oral iron supplementation.InterventionPatients will be randomly assigned (1:1) to standard care or 40 mg long-acting octreotide once every 4 weeks for 52 weeks, in addition to standard care. The follow-up period is 8 weeks.Main outcome measuresThe primary outcome is the difference in the number of blood and iron infusions between the year prior to inclusion and the treatment period of 1 year. Important secondary outcomes are the per cent change in the number of rebleeds from baseline to end point, adverse events and quality of life.Ethics and disseminationThe trial received ethical approval from the Central Committee on Research Involving Human Subjects and from the local accredited Medical Research Ethics Committee of the region Arnhem-Nijmegen, the Netherlands (reference number: 2014-1433). Results will be published in a peer-reviewed journal and presented at international conferences.Trial registration numberNCT02384122; Pre-results.