The value of fast-acting insulin aspart compared with insulin aspart for patients with diabetes mellitus treated with bolus insulin from a UK health care system perspective.

BACKGROUND: Fast-acting insulin aspart is a new formulation of the rapid-acting insulin analogue insulin aspart and represents an advancement over current rapid-acting insulin analogues in terms of onset of action and postprandial glucose control. The objective of the current analysis was to demonstrate the cost impact of prescribing fast-acting insulin aspart instead of insulin aspart, to highlight the value of fast-acting insulin aspart for the treatment of people with diabetes requiring mealtime insulin. METHODS: A cost-impact analysis was conducted from the perspective of the UK National Health Service (NHS). The analysis excluded patients' out-of-pocket expenses, carers' costs and lost productivity. The time horizon of the analysis was 1 year, and no discounting was therefore applied. RESULTS: The displacement of insulin aspart with fast-acting insulin aspart is cost neutral for the UK NHS. Fast-acting insulin aspart is at price parity to insulin aspart in terms of the vial and Penfill® cartridge and is available in the FlexTouch® pen at the same price as the insulin aspart FlexPen® (and thus cheaper than the insulin aspart FlexTouch® pen). Patients using the insulin aspart FlexPen® will be upgraded to the FlexTouch® pen device, which is preferred by patients and healthcare professionals, on switching to fast-acting insulin aspart, at no additional cost. CONCLUSIONS: Fast-acting insulin aspart offers additional clinical benefit but at no additional cost when compared with insulin aspart, and thus provides value to the UK NHS.

Hypoglycemia Event Rates: A Comparison Between Real-World Data and Randomized Controlled Trial Populations in Insulin-Treated Diabetes.

INTRODUCTION: Hypoglycemia is the most common adverse effect of diabetes therapy, particularly insulin treatment. Hypoglycemia is associated with considerable clinical and economic burden, and may be under-reported. The aim of this study was to com pare the frequency of hypoglycemic events reported in real-world settings with those reported in clinical trials. METHODS: We conducted a structured literature review in PubMed to identify hypoglycemic event rates in patients with type 1 diabetes mellitus (T1DM) and insulin-treated type 2 diabetes mellitus (T2DM) from real-world data (RWD) and randomized controlled trials (RCTs). The search was restricted to English language, full-text publications from 2010 onwards, reporting on treatment of T1DM or T2DM with basal only, basal-bolus, or premix insulin. RESULTS: The final dataset included 30 studies (11 RWD studies and 19 RCTs). Six studies (RWD, n = 2; RCT, n = 4) reported hypoglycemia event rates in people with T1DM. For all reported categories of hypoglycemia (severe, non-severe, and nocturnal), rates were consistently higher in RWD studies compared with RCTs. Twenty-five studies (RWD, n = 10; RCT, n = 15) reported hypoglycemia event rates in people with insulin-treated T2DM. For T2DM basal-oral therapy; the highest rates were observed in RWD studies, although there was an overlap with RCT rates. For basal-bolus therapy, there was considerable between-study variability but higher rates of severe and non-severe hypoglycemia were generally observed in RWD studies. For T2DM premix insulin, reported rates of hypoglycemia in RWD studies and RCTs were similar. CONCLUSION: We found that higher rates of hypoglycemia are observed in real-world settings compared with clinical trial settings, although there is a large degree of overlap. Due to the inherent constraints of RCTs, they are likely to underestimate the burden of hypoglycemia in clinical practice. Further, high-quality RWD are needed to determine a more accurate incidence of hypoglycemia in clinical practice.

Cost effectiveness of tenofovir disoproxil fumarate for the treatment of chronic hepatitis B from a Canadian public payer perspective.

INTRODUCTION: Previous research has demonstrated that tenofovir disoproxil fumarate (DF) is the most cost-effective nucleos(t)ide treatment for chronic hepatitis B (CHB) in the UK, Spain, Italy and France. However, to our knowledge, no published studies have yet evaluated the cost effectiveness of any treatments for CHB in a Canadian setting, where relative prices and management of CHB differ from those in Europe. AIM: Our objective was to determine the cost effectiveness of tenofovir DF compared with other nucleos(t)ide therapies licensed for CHB in Canada from the perspective of publicly funded healthcare payers. METHODS: A Markov model was used to calculate the costs and benefits of nucleos(t)ide therapy in three groups of patients with hepatitis B e antigen (HBeAg)-positive and -negative CHB: nucleos(t)ide-naive patients without cirrhosis; nucleos(t)ide-naive patients with compensated cirrhosis; and lamivudine-resistant patients. Disease progression was modelled as annual transitions between 18 disease states. Transition probabilities, quality of life and costs were based on published studies. Health benefits were measured in QALYs. The reference year for costs was 2007 and costs and outcomes were discounted at 5% per annum. RESULTS: First-line tenofovir DF was the most effective nucleos(t)ide strategy for managing CHB, generating 6.85-9.39 QALYs per patient. First-line tenofovir DF was also the most cost-effective strategy in all patient subgroups investigated, costing between $Can43,758 and $Can48,015 per QALY gained compared with lamivudine then tenofovir. First-line tenofovir DF strongly dominated first-line entecavir. Giving tenofovir DF monotherapy immediately after lamivudine resistance developed was less costly and more effective than any other active treatment strategy investigated for lamivudine-resistant CHB, including second-line use of adefovir or adefovir + lamivudine. Probabilistic sensitivity analysis demonstrated 50% confidence that first-line tenofovir DF is the most cost-effective nucleos(t)ide strategy for treatment-naive patients with CHB, at a $Can50,000 per QALY threshold, and confirmed that first-line tenofovir DF has the highest expected net benefits. CONCLUSIONS: First-line tenofovir DF appears to be the most cost-effective nucleos(t)ide treatment for both cirrhotic and non-cirrhotic CHB patients in Canada, providing that society is willing to pay at least $Can48,015 per QALY gained, although sensitivity analyses highlighted uncertainty around the results.

Hypoglycemia: an overview of fear of hypoglycemia, quality-of-life, and impact on costs.

BACKGROUND: The clinical goal in the treatment of diabetes is to achieve good glycemic control. Tight glycemic control achieved with intensive glucose lowering treatment reduces the risk of long-term micro- and macro-vascular complications of diabetes, resulting in an improvement in quality-of-life for the patient and decreased healthcare costs. The positive impact of good glycemic control is, however, counterbalanced by the negative impact of an increased incidence of hypoglycemia. METHODS: A search of PubMed was conducted to identify published literature on the impact of hypoglycemia, both on patient quality-of-life and associated costs to the healthcare system and society. RESULTS: In people with type 1 or type 2 diabetes, hypoglycemia is associated with a reduction in quality-of-life, increased fear and anxiety, reduced productivity, and increased healthcare costs. Fear of hypoglycemia may promote compensatory behaviors in order to avoid hypoglycemia, such as decreased insulin doses, resulting in poor glycemic control and an increased risk of serious health consequences. Every non-severe event may be associated with a utility loss in the range of 0.0033-0.0052 over 1 year, further contributing to the negative impact. LIMITATIONS: This review is intended to provide an overview of hypoglycemia in diabetes and its impact on patients and society, and consequently it is not a comprehensive evaluation of all studies reporting hypoglycemic episodes. CONCLUSION: To provide the best possible care for patients and a cost-effective treatment strategy for healthcare decision-makers, a treatment that provides good glycemic control with a limited risk of hypoglycemia would be a welcome addition to diabetes management options.

Mixed treatment comparison meta-analysis evaluating the relative efficacy of nucleos(t)ides for treatment of nucleos(t)ide-naive patients with chronic hepatitis B.

BACKGROUND/AIMS: Five nucleoside/nucleotide treatments are now available for chronic hepatitis B (CHB). This meta-analysis aimed to assess the relative efficacy of adefovir, entecavir, lamivudine, telbivudine, tenofovir disoproxil fumarate (TDF), and nucleos(t)ide combinations in the treatment of CHB. METHODS: A systematic review of MEDLINE and the Cochrane library was conducted to identify all studies evaluating these nucleos(t)ides in adults with CHB. Randomized controlled trials were included in the meta-analysis if they reported the proportion of patients with undetectable hepatitis B virus (HBV) DNA or hepatitis B e antigen (HBeAg) loss/seroconversion at 1 year. Bayesian mixed treatment comparison meta-analyses were conducted in WinBUGS to assess relative efficacy. RESULTS: A random-effects meta-analysis of trials on treatment-naive patients with HBeAg-positive CHB demonstrated that 94% of patients will achieve HBV DNA < 300 copies/ml after 1 year with TDF, compared with 73% for entecavir, 50% for adefovir, and 38% for lamivudine. There was a 97.7% probability that TDF enabled a greater proportion of patients to achieve HBV DNA < 300 copies/ml at 1 year than all other treatments considered in the analysis. TDF was significantly superior to all nucleos(t)ides for this outcome at the 0.05 level. There were no statistically significant differences between nucleos(t)ides in HBeAg seroconversion at 1 year, based on a fixed-effects meta-analysis in the same population. More trials on HBeAg-negative and drug-resistant patients are required to facilitate meta-analyses for these subgroups. CONCLUSIONS: In nucleos(t)ide-naive patients with HBeAg-positive CHB, TDF is associated with the highest probability of achieving undetectable HBV DNA at 1 year of all nucleos(t)ides considered.

Enoxaparin is a cost-effective adjunct to fibrinolytic therapy for ST-elevation myocardial infarction in contemporary practice.

INTRODUCTION: In patients receiving fibrinolytic therapy for ST-elevation myocardial infarction (STEMI), adjunct treatment with enoxaparin has been shown to provide superior net clinical benefit compared with unfractionated heparin (UFH) in the Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment - Thrombolysis in Myocardial Infarction (ExTRACT-TIMI) 25 study. The objective of this study was to compare the cost effectiveness of enoxaparin and UFH strategies. METHODS: A cost-utility analysis was conducted using a two-stage model: (1) A 30-day decision tree analytical model for the acute treatment phase, and (2) a lifetime Markov model (from 30 days post-STEMI until death) populated using patient survival data. RESULTS: Assuming treatment continuation for 7 days, the mean day 1-30 incremental cost associated with enoxaparin was pound 49 per patient, and mean lifetime incremental cost was pound 592 per patient ( pound 91,091 vs. pound 90,499, respectively). Given an additional 0.048 life years gained per patient with enoxaparin, the cost per life year saved was pound 12,353, and given an additional 0.038 quality-adjusted life years (QALY) per patient with enoxaparin, the cost per QALY was pound 15,413. In an alternative scenario, reflecting contemporary practice assuming early treatment discontinuation at 48 hours, for example following urgent revascularization, the incremental cost per QALY was pound 13,556. CONCLUSION: The use of an enoxaparin versus UFH strategy in patients receiving fibrinolytic therapy for STEMI, whether continued for 7 days or discontinued early, for example following urgent revascularization, is cost effective at a pound 20,000 willingness-to-pay threshold.

The cost-effectiveness of somatropin treatment for short children born small for gestational age (SGA) and children with growth hormone deficiency (GHD) in Sweden.

OBJECTIVE: Reduction in health-related quality of life is common in children born small for gestational age (SGA) or children with growth hormone deficiency (GHD). Growth hormone treatment with somatropin in these children leads to normalisation of height. The aim of this study was to determine whether somatropin is a cost-effective treatment option for short children born SGA and GHD children in Sweden. METHODS: A Markov decision-tree model was used to calculate the relative costs and health benefits associated with somatropin treatment over the lifetime of SGA and GHD children, compared with no treatment. The analysis was undertaken from a Swedish Health Service perspective. As quality-adjusted life-year (QALY) data were not obtained directly in the clinical studies, a degree of uncertainty is related to these results. Sensitivity analyses assessed the degree of uncertainty surrounding central parameters. RESULTS: For short children born SGA, somatropin treatment was associated with an additional 3.29 QALYs at an incremental cost of 792,489 SEK (Swedish Krona), compared with no treatment. For GHD, somatropin treatment resulted in 3.25 additional QALYs at an incremental cost of 391,291 SEK. This equates to an incremental cost per QALY of 240,831 SEK and 120,494 SEK for SGA and GHD, respectively, below a cost-effectiveness threshold of 500,000-600,000 SEK/QALY. CONCLUSIONS: Somatropin is a cost-effective treatment strategy in Sweden for children with GHD and SGA. To overcome present study limitations future clinical research should incorporate appropriate quality of life questionnaires.

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.

Genome-wide analysis of copy number changes and loss of heterozygosity in myelodysplastic syndrome with del(5q) using high-density single nucleotide polymorphism arrays.

BACKGROUND: We undertook a genome wide single nucleotide polymorphism analysis of a spectrum of patients with myelodysplastic syndrome del(5q) in order to investigate whether additional genomic abnormalities occur. Single nucleotide polymorphism array analysis has been shown to detect not only gene deletions but also regions of uniparental disomy that can pinpoint particular regions for mutation analysis. DESIGN AND METHODS: We studied 42 cases of myelodysplastic syndrome with del(5q), comprising 21 patients with 5q- syndrome and 21 with del(5q) (not 5q- syndrome), and 45 healthy controls by genome wide single nucleotide polymorphism analysis with the 50K Affymetrix single nucleotide polymorphism arrays. RESULTS: The del(5q) was characterized in all cases. The commonly deleted region of the 5q- syndrome extends between the genes SH3TC2 (proximal boundary) and GLRA1 (distal boundary) and measures 2.9 Mb. Copy number changes in addition to the del(5q) were observed in 10 of 21 patients with del(5q) myelodysplastic syndrome but in none of the patients with the 5q- syndrome. A total of 63 regions of uniparental disomy greater than 2 Mb were detected in 40 of 42 patients, dispersed on 18/23 chromosomes. In the 5q- syndrome group 31 regions of uniparental disomy were identified in 19 of 21 patients, the largest one being 7.6 Mb. All 21 patients with del(5q) myelodysplastic syndrome had uniparental disomy; in total 32 regions of uniparental disomy were identified in the 21 patients, including six regions of uniparental disomy > 10 Mb. Eight recurrent regions of uniparental disomy were observed among the 42 patients. For eight patients we had T-cell DNA as a germline control and four recurrent regions of uniparental disomy were identified that were present only in the neutrophil and not T-cell DNA. One small region of uniparental disomy at 10p12.31-p12.2 was observed in four patients with the 5q- syndrome. CONCLUSIONS: This study shows that regions of uniparental disomy greater than 2 Mb are found in the 5q-syndrome and del(5q) myelodysplastic syndrome, although large regions of uniparental disomy (>10 Mb) are only found in the latter group. The recurrent regions of uniparental disomy may indicate the position of novel leukemia-associated genes.

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.

Gene expression profiling of CD34+ cells in patients with the 5q- syndrome.

The transcriptome of the CD34+ cells was determined in a group of 10 patients with the 5q- syndrome using a comprehensive array platform, and was compared with the transcriptome of CD34+ cells from 16 healthy control subjects and 14 patients with refractory anaemia and a normal karyotype. The majority of the genes assigned to the commonly deleted region (CDR) of the 5q- syndrome at 5q31-q32 showed a reduction in expression levels in patients with the 5q- syndrome, consistent with the loss of one allele. Candidate genes showing haploinsufficiency in the 5q- syndrome included the tumour suppressor gene SPARC and RPS14, a component of the 40S ribosomal subunit. Two genes mapping to the CDR, RBM22 and CSNK1A1, showed a >50% reduction in gene expression, consistent with the downregulation of the remaining allele. This study identified several significantly deregulated gene pathways in patients with the 5q- syndrome and gene pathway analysis data supports the proposal that SPARC may play a role in the pathogenesis of the 5q- syndrome. This study suggests that several of the genes mapping to the CDR of the 5q- syndrome play a role in the pathogenesis of this disorder.

Gene expression profiles of CD34+ cells in myelodysplastic syndromes: involvement of interferon-stimulated genes and correlation to FAB subtype and karyotype.

To gain insight into the poorly understood pathophysiology of the myelodysplastic syndromes (MDSs), we have determined the gene expression profiles of the CD34+ cells of 55 patients with MDS by using a comprehensive array platform. These profiles showed many similarities to reported interferon-gamma-induced gene expression in normal CD34+ cells; indeed the 2 most up-regulated genes, IFIT1 and IFITM1, are interferon-stimulated genes (ISGs). Alterations in the expression of ISGs may play a role in the hematologic features of MDS, such as peripheral blood cytopenias. Up-regulation of IFIT1 is a potential diagnostic marker for MDS. We determined whether distinct gene expression profiles were associated with specific FAB and cytogenetic groups. CD34+ cells from patients with refractory anemia with ringed sideroblasts (RARS) showed a particular gene expression profile characterized by up-regulation of mitochondrial-related genes and, in particular, of those of heme synthesis (eg, ALAS2). CD34+ cells from patients with the del(5q) had a distinct gene expression profile, characterized by down-regulation of genes assigned to 5q, and up-regulation of the histone HIST1 gene cluster at chromosome 6p21 and of genes related to the actin cytoskeleton. This study provides important and new insights into the pathophysiology of MDS.

Gene expression profiling in the myelodysplastic syndromes.

The myelodysplastic syndromes (MDS) are a heterogeneous group of haematopoietic malignancies, characterized by blood cytopenias, ineffective hematopoiesis and hypercellular bone marrow. Several genetic alterations have been reported in MDS but these are not MDS-specific and the underlying molecular causes of the disease remain poorly understood. Gene expression microarray technology allows the simultaneous parallel analysis of many thousands of genes and has already provided novel insights into cancer pathogenesis. In this review we discuss the results of several recent studies which utilize the enormous power of microarray technology for the study of MDS. Several exciting findings have emerged from these early studies that highlight the potential of this technology to further our understanding of the molecular pathogenesis of this disorder. It is clear, however, that these findings should be confirmed in larger sets of MDS patients.

Low expression of the putative tumour suppressor gene gravin in chronic myeloid leukaemia, myelodysplastic syndromes and acute myeloid leukaemia.

The putative tumour suppressor gene gravin is down-regulated in several solid tumours and is implicated in tumorigenesis. We have evaluated the expression levels of the gravin gene in the CD34(+)/blast cells of a range of myeloid malignancies as compared with controls using real-time quantitative polymerase chain reaction (PCR). Gravin was markedly down-regulated in 41 of 41 patients with acute myeloid leukaemia (AML), nine of 10 patients with myelodysplastic syndromes (MDS) and 33 of 33 patients with chronic myeloid leukaemia (CML), of whom 24 were in blast crisis (BC). We have shown that gravin is consistently down-regulated in the CD34(+)/blast cells of myeloid malignancies and may play a role in the molecular pathogenesis of these disorders.

NRAS, FLT3 and TP53 mutations in patients with myelodysplastic syndrome and a del(5q).

Mutations of the NRAS and TP53 genes and internal tandem duplication (ITD) of the FLT3 gene are among the most frequently observed molecular abnormalities in the myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). We sought to determine the incidence of these abnormalities in patients with MDS and a 5q deletion. NRAS and FLT3 mutations are uncommon in MDS patients with a 5q deletion and TP53 mutation is associated with the more advanced MDS subtypes.

Gene expression profiling in the myelodysplastic syndromes using cDNA microarray technology.

The myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal disorders of the haematopoietic stem cell and primarily involve cells of the myeloid lineage. Using cDNA microarrays comprising 6000 human genes, we studied the gene expression profiles in the neutrophils of 21 MDS patients, seven of which had the 5q- syndrome, and two acute myeloid leukaemia (AML) patients when compared with the neutrophils from pooled healthy controls. Data analysis showed a high level of heterogeneity of gene expression between MDS patients, most probably reflecting the underlying karyotypic and genetic heterogeneity. Nevertheless, several genes were commonly up or down-regulated in MDS. The most up-regulated genes included RAB20, ARG1, ZNF183 and ACPL. The RAB20 gene is a member of the Ras gene superfamily and ARG1 promotes cellular proliferation. The most down-regulated genes include COX2, CD18, FOS and IL7R. COX2 is anti-apoptotic and promotes cell survival. Many genes were identified that are differentially expressed in the different MDS subtypes and AML. A subset of genes was able to discriminate patients with the 5q- syndrome from patients with refractory anaemia and a normal karyotype. The microarray expression results for several genes were confirmed by real-time quantitative polymerase chain reaction. The MDS-specific expression changes identified are likely to be biologically important in the pathophysiology of this disorder.

Novel translocations that disrupt the platelet-derived growth factor receptor beta (PDGFRB) gene in BCR-ABL-negative chronic myeloproliferative disorders.

The BCR-ABL-negative chronic myeloproliferative disorders (CMPD) and myelodysplastic/myeloproliferative diseases (MDS/MPD) are a spectrum of related conditions for which the molecular pathogenesis is poorly understood. Translocations that disrupt and constitutively activate the platelet-derived growth factor receptor beta(PDGFRB) gene at chromosome band 5q33 have been described in some patients, the most common being the t(5;12)(q33;p13). An accurate molecular diagnosis of PDGFRB-rearranged patients has become increasingly important since recent data have indicated that they respond very well to imatinib mesylate therapy. In this study, we have tested nine patients with a CMPD or MDS/MPD and a translocation involving 5q31-33 for disruption of PDGFRB by two-colour fluorescence in situ hybridization (FISH) using differentially labelled, closely flanking probes. Normal control interphase cells gave a false positive rate of 3% (signals more than one signal width apart). Six patients showed a pattern of one fused signal (from the normal allele) and one pair of signals separated by more than one signal width in > 85% of interphase cells, indicating that PDGFRB was disrupted. These individuals had a t(1;5)(q21;q33), t(1;5)(q22;q31), t(1;3;5)(p36;p21;q33), t(2;12;5)(q37;q22;q33), t(3;5) (p21;q31) and t(5;14)(q33;q24) respectively. The remaining three patients with a t(1;5)(q21;q31), t(2;5)(p21;q33) and t(5;6)(q33;q24-25) showed a normal pattern of hybridization, with > or = 97% interphase cells with two fusion signals. We conclude that two-colour FISH is useful to determine the presence of a PDGFRB rearrangement, although, as we have shown previously, this technique may not detect subtle complex translocations at this locus. Our data indicate that several PDGFRB partner genes remain to be characterized.

Narrowing and genomic annotation of the commonly deleted region of the 5q- syndrome.

The 5q- syndrome is the most distinct of the myelodysplastic syndromes, and the molecular basis for this disorder remains unknown. We describe the narrowing of the common deleted region (CDR) of the 5q- syndrome to the approximately 1.5-megabases interval at 5q32 flanked by D5S413 and the GLRA1 gene. The Ensembl gene prediction program has been used for the complete genomic annotation of the CDR. The CDR is gene rich and contains 24 known genes and 16 novel (predicted) genes. Of 40 genes in the CDR, 33 are expressed in CD34(+) cells and, therefore, represent candidate genes since they are expressed within the hematopoietic stem/progenitor cell compartment. A number of the genes assigned to the CDR represent good candidates for the 5q- syndrome, including MEGF1, G3BP, and several of the novel gene predictions. These data now afford a comprehensive mutational/expression analysis of all candidate genes assigned to the CDR.