Splicing Factor 3b Subunit 1 (SF3B1) Heterozygous Mice Manifest a Hematologic Phenotype Similar To Low Risk Myelodysplastic Syndromes With Ring Sideroblasts

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 259-259 ◽  
Author(s):  
Valeria Visconte ◽  
Heesun J. Rogers ◽  
Ali Tabarroki ◽  
Li Zhang ◽  
Yvonne Parker ◽  
...  
Keyword(s):  
Mouse Model ◽  
Myelodysplastic Syndromes ◽  
Low Risk ◽  
Wilcoxon Test ◽  
Chromosome 1 ◽  
Refractory Anemia ◽  
Mrna Levels ◽  
Genetically Engineered Mice ◽  
Significant Difference

Abstract The link between SF3B1 mutation and the ring sideroblast (RS) phenotype in myelodysplastic syndromes (MDS) was solidified by the identification of RS in Sf3b1 heterozygous (Sf3b1+/-) mice. The identification of SF3B1 mutations in refractory anemia with RS (RARS) and RARS with thrombocytosis (RARS-T) showed the importance of RNA splicing in MDS biology. Furthermore, it opened the possibility of targeted therapy using spliceosome inhibitors in RARS/-T. However, many questions remain unanswered in linking SF3B1 dysfunction to MDS biology like the downstream targets of this gene. The identification of a robust murine model is essential to study a specific molecularly defined disease-phenotype and develop targeted therapies. We identified occasional RS in the bone marrow (BM) of Sf3b1+/- which are rarely found in current mouse models of MDS (Beachy SH, Hematol Oncol Clin North Am, 2010). However, aside from RS in the BM no other MDS features were found. Sf3b1+/- mice were originally engineered as a means to study the interaction between polycomb (PcG) genes and other protein-complexes (Isono K, Genes Dev, 2005). Homozygous Sf3b1-/- mice died at the stage of pre-implantation of the embryos while Sf3b1+/- appear healthy. Several tools have been tested to model MDS in genetically engineered mice targeting key genes in MDS. However, the creation of an ideal mouse model resembling distinct morphologic MDS subtypes is still lacking. To define a mouse model useful for preclinical therapeutic studies, we evaluated the hematologic features of Sf3b1+/- and Sf3b1+/+ mice during a long term follow-up. Five Sf3b1+/- and 5 Sf3b1+/+ mice were followed over time until 12 months of age. Blood was drawn from the retro-orbital vein every month starting from 6 months of age. Using two-sample Wilcoxon test we compared standard hematologic parameters finding a significant difference over the time between Sf3b1+/- and Sf3b1+/+: hemoglobin (g/dL) 6.9 ±0.73 vs 10.0 ±1.6 (P=0.008), red blood cells (M/uL) 8.3±0.5 vs 5.9±1.0 (P=0.008), platelets (K/uL) 731±105 vs 579±93 (P=0.008), and mean corpuscular volume (fL) 47.8±1.5 vs 45.1±1.1 (P=0.032). We did not detect any significant difference in other parameters although lymphocytes were more represented vs neutrophils, eosinophils and monocytes in Sf3b1+/- vs Sf3b1+/+ (6.3K/uL ±3.1 vs 5.8 ±1.8; P=1). Analysis of the BM, showed no difference in cell number between Sf3b1+/- (n=7) and Sf3b1+/+ (n=7) (44.1±9.1 vs 43.2 ±11; P=0.62). However, distinct dyserythropoiesis such as nuclear budding or irregular nuclei in Wright-Giemsa and occasional RS in Prussian blue stains were noted in Sf3b1+/- which were not present in Sf3b1+/+. In support of the iron overload seen in SF3B1 mutant patients (pts), a similar observation was made in Sf3b1+/- by light microscopy and rhodamine based- flow cytometry to quantify mitochondrial iron (Visconte, Abstract #64897). We also characterized the transcriptome of Sf3b1+/- and Sf3b1+/+. Total RNA was isolated from BM of age/gender matched mice, polyA cDNA was prepared from 3ug of RNA and Mouse RNA-sequencing was run on Illumina HiSeq2000. 200 exons were found differentially used in Sf3b1+/- vs Sf3b1+/+. Chromosome 1 contains the highest number of genes with at least 1 exon alternatively used similar to what we observed in SF3B1 mutant pts. In total 22 genes showed stronger differential expression in Sf3b1+/- vs Sf3b1+/+. Sf3b1 was down-regulated as expected (MFC: 0.74) in Sf3b1+/-. Studies in Sf3b1+/- mice show that Sf3b1 protein physically interacts with Class II PcG proteins (PRC1) which are relevant in MDS. When we interrogated PcG genes and others, we found lower mRNA levels of ezh2 (MFC: 0.06) and npm1 and tpr53 (MFC: 0.01 and 0.28) and no difference in asxl1 and runx1 (MFC:1.22 and 1.1) in Sf3b1+/- vs Sf3b1+/+. Jak2, dock8, and uhrf2 showed significant (P=.0003) higher expression in Sf3b1+/-. MDS is a heterogeneous disease characterized by genetic and non-genetic causes. Introduction of secondary events implicated in MDS pathogenesis can modify the phenotype of Sf3b1+/- mice. In sum, Sf3b1+/- mice after 6 months of follow-up developed macrocytic anemia, thrombocytosis, RS and dyserythropoiesis akin to human RARS/-T. Furthermore, transcriptome analysis shows exon usage/ gene expression changes similar to human SF3B1 mutants lending support that Sf3b1+/- can serve as a mouse model for studying the biology of human low risk MDS specifically that of RARS/-T. Disclosures: No relevant conflicts of interest to declare.

Human Leukocyte Antigen DR15 in Patients with Myelodysplastic Syndromes (MDS) – A Study in Chinese Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2463-2463
Author(s):  
Qiong Liao Master ◽  
Yan Zhang ◽  
Xiao Li ◽  
Zheng Zhang ◽  
Shaoxu Ying ◽  
...  
Keyword(s):  
Human Leukocyte Antigen ◽  
Myelodysplastic Syndromes ◽  
Peripheral Blood ◽  
Human Leukocyte ◽  
Low Risk ◽  
Chinese Patients ◽  
Refractory Anemia ◽  
Healthy Controls ◽  
Leukocyte Antigen ◽  
Significant Difference

Abstract We investigate the frequency of the human leukocyte antigen DR15 (HLA-DR15) allele in patients with myelodysplastic syndromes (MDS). We used polymerase chain reaction-sequence-specific primers (PCR-SSP) to detect HLA-DR15 in the peripheral blood of patients with MDS(n = 76) and healthy controls (n = 227). The frequency of HLA-DR15 in MDS patients (40.8%) was significantly higher than in controls (13.7%; P < 0.01). The diagnoses of refractory anemia/refractory anemia with ring sideroblasts (RA/RARS) accounted for 77.4% (24/31) and 62.2% (28/45) of the DR15-positive and the DR15-negative patients, respectively (difference not statistically significant). Although no statistically significant difference was observed, some trends were observed: IPSS low-risk MDS (IPSS score, ≤1) accounted for 80.6% of the DR15-positive patients compared to 64.4% among the DR15-negative patients. However, the difference between the numbers of DR15-positive and DR15-negative patients with chromosomal abnormalities was not statistically significant. Nevertheless, poor risk chromosome abnormalities (according to IPSS), were present in only 1 DR15-positive patient, while such abnormalities were present in 8 DR15-negative patients. In addition, the proportions of DR15-positive and DR15-negative patients with more than 5% blasts in marrow were 19.4% and 31.1%, respectively. Peripheral blood pancytopenia occurred in 51.6% of DR15-positive, and in 40.0% of DR15-negative patients. Although the HLA-DR15 allele appeared to be present more frequently in patients less than 60 years of age, this association was not significant. The frequency of HLA-DR15 was significantly higher in patients with MDS than in healthy controls suggesting the possibility that HLA-DR15 is associated with an enhanced susceptibility to develop MDS. The fact that HLA-DR15 was predominantly noted in patients with RA/RARS and low IPSS scores, suggested that HLA-DR15 might be associated more with bone marrow failure and less with leukemic transformation. clinical/experimental characteristics in HLA-DR15 positive or negative MDS patients Cohort HLA-DR15 positive(n=31) HLA-DR15 negative(n=45) P value RA/RARS(case/%) 24/31(77.4) 28/45(62.2) 0.161 Low risk (IPSS≤1) (case/%) 25/31(80.6) 29/45(64.4) 0.126 Karyotype abnormal(case/%) 13/31(41.9) 18/45(40.0) 0.866 Poor chromosome(case/%) 1/31(3.2) 8/45(17.8) 0.117 Blast>5%(case/%) 6/31(19.4) 14/45(31.1) 0.253 Pancytopenia(case/%) 16/31(51.6) 18/45(40.0) 0.317 Male patients(case/%) 17/31(54.8) 25/45(55.6) 0.951 age(<60 years) (case/%) 20/31(64.5) 20/45(44.4) 0.085 Figure Figure Figure Figure

Transfusion Practices in Myelodysplastic Syndromes: Preliminary Results of An Epidemiologic and Economical Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4336-4336
Author(s):  
Matthieu Filloux ◽  
Adrien Chauchet ◽  
Yvan Beaussant ◽  
Chrystelle Vidal ◽  
Franck Leroux ◽  
...  
Keyword(s):  
Myelodysplastic Syndromes ◽  
Transfusion Requirement ◽  
Conflicts Of Interest ◽  
Age Groups ◽  
Iron Chelation ◽  
Low Risk ◽  
Economic Study ◽  
Transfusion Threshold ◽  
Significant Difference

Abstract Abstract 4336 Background Despite the improvements and promises of novel agents (demethylating and erythropoiesis stimulating agents), red blood cells (RBC) and platelets transfusion remains frequent and essential in the management of myelodysplastic syndromes (MDS). Reducing patients’ dependence to transfusion is a major outcome, linked with the disease prognosis, patients’ quality of life and economical issues. Few data in the literature have described transfusions practices and requirements in MDS patients. We report here an epidemiological study of the transfusion practices in our center and try to build an economical evaluation of direct transfusions costs. Design and Methods We conducted a retrospective, descriptive study including all new patients diagnosed with MDS in the department of haematology of Besan□ on between 2006 and 2009. Patients were classified as high risk (HR) MDS when IPSS was ≥ 1.5, and as low risk (LR) when IPSS was ≤ 1. We compared HR and LR groups and four categories of age (≤68; [68–76]; [76–83] and >83 years) according to transfusion data. The economic study compared direct costs of RBC transfusions and erythroipoiesis-stimulating agents for LR and HR patients, including the costs of hospital stays. Materials, transport, medical examinations, doctors’ and nurses’ wages and iron chelation were not considered in this analysis. T-test and χ2-test were used for comparisons. Results 205 patients were analysed, median age at diagnosis was 74.3 years (table 1), with a predominance of men (sex ratio 1.33). IPSS score was available for 75% of patients (n=154), 111 LR patients and 43 HR patients. Median follow-up was 32 months [10–57]. Twenty-three patients (11%) developed a secondary acute leukaemia and 11 (5%) received allogeneic stem cell transplantation. At diagnosis, hemoglobin (Hb) level was not significantly different between HR and LR patients. Platelets level was lower in the HR vs LR (109 vs. 178 G/L respectively, p<0.0001). 60.5% of patients (n=124/205) received labile blood products during the follow-up, more frequently RBC than platelets (87.5% vs. 12.5% respectively). The mean Hb threshold at transfusion was 8.1 g/dl without any significant difference between neither age groups nor IPSS; age did not influenced transfusion requirement (Table 2). In comparison to HR patients, LR patients were less transfused (55 vs. 79%, p<0.006, table 2), and had longer mean intervals between transfusions (32.5 vs. 16.9 days, p<0.001). Furthermore, a progressive shortening of transfusion intervals was observed for both groups along the time; this progression was faster for HR patients. The anti-erythrocyte immunization rates, excluding anti-RH or anti-Kell, was 6.7%. Economical analysis showed that annual costs of RBC transfusion were 11,409 euros in LR patients and 21,945 euros in HR patients versus 11,492 euros for EPO. Conclusion In our study, neither transfusion requirement nor transfusion threshold were correlated with age, whereas both were affected by IPSS. Furthermore, age did not appear to be a predictive factor concerning the transfusion dependence. Despite its limits, the economic study reveals that EPO and transfusion's annual costs are similar in low risk patients. Updated data will be presented on EPO and 5-azacytidine use in our cohort to assess their impact on transfusion practices. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Postoperative craniospinal radiotherapy of medulloblastoma in children and young adults

2003 ◽  
Vol 131 (5-6) ◽  
pp. 226-231
Author(s):  
Ivana Golubicic ◽  
Jelena Bokun ◽  
Marina Nikitovic ◽  
Jasmina Mladenovic ◽  
Milan Saric ◽  
...  
Keyword(s):  
High Risk ◽  
Brain Stem ◽  
Wilcoxon Test ◽  
Time Interval ◽  
Tumor Removal ◽  
Shunt Placement ◽  
Craniospinal Radiotherapy ◽  
Number Of Patients ◽  
Significant Difference

PURPOSE The aim of this study was: 1. to evaluate treatment results of combined therapy (surgery, postoperative craniospinal radiotherapy with or without chemotherapy) and 2. to assess factors affecting prognosis (extend of tumor removal, involvement of the brain stem, extent of disease postoperative meningitis, shunt placement, age, sex and time interval from surgery to start of postoperative radiotherapy). PATIENTS AND METHODS During the period 1986-1996, 78 patients with medulloblastoma, aged 1-22 years (median 8.6 years), were treated with combined modality therapy and 72 of them were evaluable for the study end-points. Entry criteria were histologically proven diagnosis, age under 22 years, and no history of previous malignant disease. The main characteristics of the group are shown in Table 1. Twenty-nine patients (37.2%) have total, 8 (10.3%) near total and 41 (52.5%) partial removal. Seventy-two of 78 patients were treated with curative intent and received postoperative craniospinal irradiation. Radiotherapy started 13-285 days after surgery (median 36 days). Only 13 patients started radiotherapy after 60 days following surgery. Adjuvant chemotherapy was applied in 63 (80.7%) patients. The majority of them (46 73%) received chemotherapy with CCNU and Vincristine. The survival rates were calculated with the Kaplan-Meier method and the differences in survival were analyzed using the Wilcoxon test and log-rank test. RESULTS The follow-up period ranged from 1-12 years (median 3 years). Five-year overall survival (OS) was 51% and disease-free survival (DFS) 47% (Graph 1). During follow-up 32 relapses occurred. Patients having no brain stem infiltration had significantly better survival (p=0.0023) (Graph 2). Patients with positive myelographic findings had significantly poorer survival compared to dose with negative myelographic findings (p=0.0116). Significantly poorer survival was found in patients with meningitis developing in the postoperative period, with no patient living longer than two years (p=0.0134) (Graph 3). By analysis of OS and DFS in relation to presence of the malignant cells in liquor, statistically significant difference, i. e. positive CSF cytology was not obtained, which was of statistical importance for survival (p=0.8207). Neither shunt placement nor shunt type showed any impact on survival (p=0.5307 and 0.7119, respectively). Children younger than three years had significantly poorer survival compared to those older than 16 years (p=0.0473). Although there was a better survival rate in females than in males this was not statistically significant (p=0.2386).The analysis results of treatment showed that significantly better survival occurred in patients in whom total or subtotal tumor removal was possible (p=0.0022) (Graph 4). Patients who started radiotherapy within two months after surgery have better survival, but again this was not statistically significant, probably due to the small number of patients receiving delayed radiotherapy (p=0.2231)(Graph5). CONCLUSION Based on this factors standard and high risk group could be defined. Combined chemotherapy should to be investigated particularly for high risk subgroup. Future research should be done to define new therapeutic modalities (gene therapy, compounds active in tumor antiangiogenesis etc).

scholarly journals DNA instability in low-risk myelodysplastic syndromes: refractory anemia with or without ring sideroblasts

2008 ◽  
Vol 17 (14) ◽  
pp. 2144-2149 ◽  
Author(s):  
B. Novotna ◽  
R. Neuwirtova ◽  
M. Siskova ◽  
Y. Bagryantseva
Keyword(s):  
Myelodysplastic Syndromes ◽  
Low Risk ◽  
Refractory Anemia ◽  
Dna Instability ◽  
Ring Sideroblasts

An Update on the Role of Thalidomide (THAL) in Total Therapy 2 (TT2) for Newly Diagnosed Patients with Multiple Myeloma (MM): Analysis of Subgroups Defined by Standard Prognostic Factors (SPF) and Gene Expression Profiling (GEP)-Derived Subgroups.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3389-3389 ◽  
Author(s):  
John D. Shaughnessy ◽  
Jeffrey Haessler ◽  
Jerry Zeldis ◽  
Yongsheng Huang ◽  
Fenghuang Zhan ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Risk Groups ◽  
Complete Response ◽  
Low Risk ◽  
Phase Iii ◽  
Significant Difference ◽  
And Control ◽  
Standard Risk

Abstract Background: THAL, whose activity in MM was discovered in the setting of advanced and refractory disease in the late 1990’s (Singhal, NEJM, 2000), has become the standard front-line therapy in combination with dexamethasone (DEX). In a randomized phase III tandem transplant trial, TT2, a higher complete response (CR) rate and longer event-free survival (EFS) had been observed on the THAL arm (Barlogie, NEJM, 2006). The similar overall survival (OS) on THAL and control arms had been attributed to the routine use of THAL as salvage therapy for the patients randomized to the No-THAL arm and the shorter post-relapse OS among patients randomized to the THAL arm. Patients and Methods: With a median follow-up on TT2 of 53mo, 107 patients have relapsed and 219 died. Subset analyses were performed to determine whether THAL confers an OS advantage in any subgroup of patients. Results: 6-yr EFS and OS rates are 48%/63% on THAL and 38%/58% on control arm (p=0.01/0.67). Post-relapse OS is now similar with median durations of 5.3mo/4.3mo among control/THAL arms (p=0.11). According to multivariate analyses of 11 standard prognostic factors, EFS was shorter among patients treated without THAL, in the presence of cytogenetic abnormalities (CA), B2M and LDH elevations and low albumin, whereas CR was favorable; OS was inferior with CA, high LDH, low albumin and in patients not receiving 2nd transplant or not achieving CR. Randomization to THAL was beneficial only in the >2 risk factor group: 6-yr OS was 47% in 31 patients on THAL and 12% in 31 control patients (Figure 1, p=0.01). When examined in the context of GEP (70 gene model-based high versus low risk groups) and inter-phase FISH data (amp1q21), available in 260 patients, the 57 with GEP low risk and absence of amp1q21 receiving THAL had 5-yr OS of 90% compared to 74% among 73 controls (p=0.13). Conclusion: With longer follow-up of 53mo on TT2, EFS remains superior among patients randomized to THAL; post-relapse survival is no longer inferior among those randomized to THAL; THAL benefited a high-risk subgroup with >2 standard risk factors, whereas no significant `difference has yet emerged among genetically defined subgroups. Figure Figure

Expression of WT-1 mRNA in Peripheral Blood from Myelodysplastic Syndromes

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3637-3637
Author(s):  
Hideto Tamura ◽  
Kazuo Dan ◽  
Norio Yokose ◽  
Rika Iwakiri ◽  
Masatsugu Ohta ◽  
...  
Keyword(s):  
High Risk ◽  
Mrna Expression ◽  
Myelodysplastic Syndromes ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Quantitative Polymerase Chain Reaction ◽  
Refractory Anemia ◽  
Mrna Levels ◽  
Cell Counts ◽  
Fab Classification

Abstract (INTRODUCTION) The Wilms’ tumor gene WT-1 is overexpressed in various types of solid tumor as well as in hematologic malignancies, i.e., acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic myeloid leukemia, and myelodysplastic syndromes (MDS). It was reported that WT-1 overexpression in peripheral blood (PB) and bone marrow (BM) is useful for the monitoring of minimal residual disease and early detection of relapse in AML. MDS are clonal hematologic stem cell disorders characterized by cytopenias and a risk of progression to acute leukemia. It is important for decisions on treatment strategy to assess disease progression and predict the prognosis in MDS. The aim of this study was to investigate the clinical significance of WT-1 mRNA expression in PB obtained from patients with MDS. (METHODS AND RESULTS) PB was obtained from 92 patients with MDS or leukemia transformed from MDS (AL-MDS): 40 refractory anemia (RA), 5 RA with ringed sideroblasts (RARS), 27 RA with excess blasts (RAEB), 5 RAEB in transformation (RAEB-t), and 15 AL-MDS cases in the FAB classification (RA 27, RARS 5, refractory cytopenia with multilineage dysplasia 12, RAEB-1 13, RAEB-2 14, 5q- 1, and AL-MDS 20 cases in the WHO classification). RNA was isolated from PB mononuclear cells (PBMCs) and converted into cDNA. The levels of WT-1 mRNA expression were assessed using the real-time quantitative polymerase chain reaction. We analyzed whether the level of WT-1 mRNA expression in PBMCs was associated with MDS subtype in the FAB classification, clinical characteristics (hemoglobin value, white blood cell counts, neutrophil counts, lymphocyte counts, chromosomal abnormality, number of cytopenias, blast percentages in BM, lactate dehydrogenase values, C-reactive protein values), International Prognostic Scoring System (IPSS) score, survival, and time to leukemia transformation. High expression of WT-1 mRNA, which was defined as more than 50 copies/μg mRNA according to the results of normals, was observed in 42.5%, 40.0%, 85.2%, 80.0%, and 100% of RA, RARS, RAEB, RAEB-t, and AL-MDS patients, respectively. The WT-1 mRNA levels increased with the aggressiveness of disease subtype and IPSS. FAB subtypes included RARS (mean ± SD, 129 ± 111 copies/μg), RA (220 ± 134), RAEB (5554 ± 2593), RAEB-t (14284 ± 9056), and AL-MDS (51591 ± 30309). IPSS score were divided into low/intermediate-1 risk (316 ± 136) and intermediate-2/high risk (7901 ± 3035) (P < 0.05 for RA vs RAEB, RAEB-t or AL-MDS; RAEB vs AL-MDS; and low/intermediate-1 vs intermediate-2/high risk). Furthermore, the WT-1 mRNA level was inversely correlated with the neutrophil percentage in PB and positively correlated with the blast percentage in both PB and BM. Among RA patients, those with favorable cytogenetics had lower WT-1 mRNA values compared with other patients (P < 0.05). When patients were divided into three groups based on the log value of WT-1 mRNA (<2, 2–4, and >=4), the survival times of those groups were 73.1, 55.6, and 15.3 months, respectively (P < 0.005). (CONCLUSIONS) Higher quantitative expression of WT-1 mRNA in PBMCs is associated with aggressive disease behavior in MDS patients. This may justify anti-WT-1 immunotherapy under investigation for MDS treatment (PNAS2004;101:13885–13890).

Long Term Follow up of Patients with CML in Chronic Phase Treated with First-Line Imatinib Suggests That Earlier Achievement of a Major Molecular Response Leads to Greater Stability of Response.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2113-2113 ◽  
Author(s):  
Susan Branford ◽  
Rebecca Lawrence ◽  
Andrew Grigg ◽  
John Francis Seymour ◽  
Anthony Schwarer ◽  
...  
Keyword(s):  
Chronic Phase ◽  
Low Risk ◽  
Initial Slope ◽  
Molecular Response ◽  
Average Dose ◽  
Major Molecular Response ◽  
First Line ◽  
Significant Difference

Abstract A major molecular response (MMR) by 12 or 18 months (m) of standard dose imatinib for patients (pts) with newly diagnosed chronic phase CML is associated with a low risk of progression to accelerated phase or blast crisis. Phase II/III trials suggest that MMR may be achieved earlier with higher doses of imatinib. We determined whether the timing of MMR affects the long term stability of response with regard to the acquisition of BCR-ABL mutations and/or loss of MMR (collectively defined as an “event”) for pts with up to 8 years of follow up since commencing first-line imatinib. All pts treated with 400 to 600mg of first-line imatinib who were monitored regularly at our institution for BCR-ABL levels by real-time quantitative PCR and mutation analysis by direct sequencing were evaluated: 181 pts were followed for a median of 45m (range (r) 3–96m). The event rate was compared for pts dependent on the time to MMR (≤0.1% IS (international scale)) in 6m intervals to 18m of imatinib. The events for pts with undetectable BCR-ABL (complete molecular response, CMR) were also determined. Strict sensitivity criteria were used for CMR: undetectable BCR-ABL where the sensitivity of analysis indicated BCR-ABL was &lt;0.003% IS, (equivalent to at least 4.5 log below the standardized baseline) which was confirmed on a subsequent analysis. Loss of MMR was defined as a confirmed &gt;2 fold rise from nadir to a level &gt;0.1% IS in pts who maintained imatinib dose. 144/181 pts (80%) achieved MMR at a median of 12m (r 3–53m). Consistent with other studies, maintaining a higher dose of imatinib in the first 6m of therapy was associated with a significantly higher frequency of pts achieving MMR by 6m. 118 pts received an average dose of &lt;600mg in the first 6m and 18/118 (15%) achieved MMR by 6m, whereas 63 pts received an average dose of 600mg in the first 6m and 23/63 (37%) achieved MMR by 6m, P=0.002. Mutations were detected in 14/181 pts (8%) at a median of 9m (r 3–42m). An event occurred in 8 pts with MMR at a median of 36m (r12–57m) after commencing imatinib, including one patient who had achieved CMR. Mutations were found in 4 pts and 3/4 lost MMR. The remaining 4 lost MMR without a mutation. The one patient with a mutation who did not lose MMR had a 3-fold rise in BCR-ABL at the time of mutation detection and responded to a higher imatinib dose. The other pts with mutations had therapeutic intervention upon cytogenetic relapse (2) or loss of MMR (1). The 4 pts with loss of MMR and no mutation had accelerated phase (1), cytogenetic relapse (2) and one maintained CCR with 3m of follow up. The median fold rise in BCR-ABL upon loss of MMR was 26 (r 4–220). The probability of an event if MMR was achieved by a) 6m was 0% (n=41 evaluable pts), b) &gt;6 to 12m was 12% (n=40) and c) 12 to 18m was 19% (n=33). The median follow up since MMR was achieved was not significantly different for the groups: 49m (r 3–87m), 38m (r 6–87m), 40m (r 9–78m), respectively, P=0.5. The risk of an event for pts with MMR achieved by 6m was significantly lower than in pts with MMR achieved by &gt;6 to 18m, P=0.04. CMR occurred in 55 pts who were followed for a median of 24m (r 3–55m) after its attainment. Only 1 event occurred in these 55 pts, which was at 6m after CMR was achieved and 57m after commencing imatinib. This patient had maintained MMR for 45m but loss of a major cytogenetic response occurred 6m after loss of MMR. There was a significant difference in the probability of CMR by 60m of imatinib dependent on the time to MMR, P&lt;0.0001 (Figure). All pts failed to achieve CMR by 60m if not in MMR at 18m whereas the actuarial rate of CMR at 60m was 93% in those with MMR by 6m. The initial slope of BCR-ABL decline correlated strongly with the decline over the longer term. The mean time to CMR after attainment of MMR was significantly faster for pts with MMR by 6m compared to those with MMR at &gt;6 to 12m and &gt;12 to 18m: 24m vs 37m vs 42m, respectively, P=0.001. This suggests the rate of BCR-ABL reduction below the level of MMR was faster in pts with MMR by 6m, which may be clinically beneficial as none of these pts had a subsequent event. Based on these findings we propose that inducing earlier molecular responses with higher dose imatinib or more potent kinase inhibitors may lead to more durable and deeper responses. It remains possible however, that early molecular response reflects a more biologically favourable disease rather than being the direct cause of more durable response. Finally, CMR was associated with an extremely low risk of events, making it an appropriate next target of therapy after MMR is achieved. Figure Figure

Prognostic Significance of WT1 mRNA and Anti-WT1 Antibody Levels in Peripheral Blood in Patients with Myelodysplastic Syndromes.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3821-3821
Author(s):  
Hideto Tamura ◽  
Kazuo Dan ◽  
Norio Yokose ◽  
Rika Iwakiri ◽  
Masatsugu Ohta ◽  
...  
Keyword(s):  
Immune Response ◽  
Mrna Expression ◽  
Myelodysplastic Syndromes ◽  
Peripheral Blood ◽  
Quantitative Polymerase Chain Reaction ◽  
Mrna Level ◽  
Prognostic Significance ◽  
Refractory Anemia ◽  
Mrna Levels ◽  
Disease Subtype

Abstract Abstract 3821 Poster Board III-757 (INTRODUCTION) The Wilms tumor gene (WT1) message is overexpressed in tumor cells from various solid cancers as well as hematologic malignancies including myelodysplastic syndromes (MDS). We reported previously that WT1 mRNA expression in peripheral blood mononuclear cells (PBMCs) as well as bone marrow (BM) cells increased with the aggressiveness of MDS disease subtype as defined by the French-American-British (FAB) classification and that a humoral immune response, IgG- or IgM-type anti-WT1 antibody (Ab) expression, was detected in sera from most MDS patients. In this study, we investigated whether WT1 mRNA expression and anti-WT1 Ab titers in PB were associated with prognosis in MDS patients by examining their long-term follow-up data. (METHODS AND RESULTS) (1) WT1 mRNA expression in PBMCs was examined in 80 patients: 35 with refractory anemia (RA); 5 with RA with ringed sideroblasts (RARS); 24 with RA with excess blasts (RAEB); 5 with RAEB in transformation (RAEB-t); and 11 with acute myeloid leukemia transformed from MDS (AML-MDS). Levels of WT1 mRNA expression were assessed using the real-time quantitative polymerase chain reaction [Tamaki H, et al, Leukemia 1999]. WT1 mRNA levels increased with the aggressiveness of disease subtype (mean: RA, 220.9; RARS, 129.4; RAEB, 5,554.3; RAEB-t, 14,284.0; AML-MDS, 56,272.7 copies/μg) and with the aggressiveness of the International Prognostic Scoring System (IPSS) category (mean: low, 114.5; intermediate-1, 360.8; intermediate-2, 12,041.6; high, 7,357.9 copies/μg) in these patients. (2) IgG- and IgM-type anti-WT1 Ab titers were determined using the dot-blot assay [Elisseeva OA, Blood 2002] in sera from 45 of the 80 patients: 15 RA; 3 RARS; 18 RAEB; 3 RAEB-t; and 6 AML-MDS. IgM and IgG WT1 Abs were detected in 31 (79.5%) and 34 (87.2%) MDS patients, and 5 (83.3%) and 6 (100%) AML-MDS patients, respectively. WT1 Abs levels were not correlated with FAB subtype, IPSS, or WT1 mRNA expression in PBMCs. (3) When patients were divided into three groups based on the WT1 mRNA level (fewer than 100 copies/μg, 100 to 10,000 copies/μg, and more than 10,000 copies/μg), their survival rates differed significantly (P = 0.0186): survival was worse in those with increased WT1 mRNA levels. Specifically, a high WT1 mRNA level was a strong predictor of rapid AML transformation even if adjusted by the IPSS (P = 0.0005). Furthermore, patients with high levels of either IgM or IgG WT1 Abs had significantly better survival compared with those whose IgM and IgG WT1 Abs values were both low (P = 0.0007) even when adjusted by the IPSS (P = 0.0019). (CONCLUSIONS) This study showed for the first time that high WT1 mRNA expression and high WT1 Ab titers in PB affected the prognosis of MDS patients negatively and positively, respectively, suggesting that an optimal immune response against WT1 may beneficial. Recently, clinical trials of WT1 peptide-based immunotherapy have been conducted for various malignancies including MDS. Our data presented here may provide a rationale for anti-WT1 immunotherapy in MDS. Disclosures: No relevant conflicts of interest to declare.

Eµ-TCL1mTerc -/- Mouse Model for Telomere Dysfunction in Chronic Lymphocytic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1724-1724
Author(s):  
Annika Scheffold ◽  
Billy Michael Chelliah Jebaraj ◽  
André Lechel ◽  
Sarah-Fee Katz ◽  
Daniela Steinbrecher ◽  
...  
Keyword(s):  
Dna Damage ◽  
Chronic Lymphocytic Leukemia ◽  
Mouse Model ◽  
Disease Burden ◽  
Disease Onset ◽  
Lymphocytic Leukemia ◽  
Telomere Dysfunction ◽  
Significant Difference ◽  
Tumor Load

Abstract Telomeres are nucleo-protein complexes at the ends of the chromosomes that play a key role in protection of the ends from being recognized as DNA damage and to prevent fusion of the chromosomes. The telomeric DNA shortens with each cell division in the absence of telomerase, due to end replication problem. In chronic lymphocytic leukemia (CLL), short telomeres were found to be associated with poor prognostic factors and poor survival in various univariable and multivariable analyses. Short telomeres in CLL are known to be frequently associated with increased DNA damage response and to undergo fusion events, conferring genomic instability. But the contribution of telomere dysfunction to CLL pathogenesis and disease progression has never been studied in vivo using mouse models. Here, we hypothesized that genomic instability resulting from telomere dysfunction could drive acquisition of genetic lesions, contributing to CLL pathogenesis, progression and disease evolution. Thus, the CLL mouse model with telomere dysfunction was generated by crossing the Eµ-TCL1 (TCL1+) mouse with mTerc-/- mouse. The first generation TCL1+ mTerc-/- (G1) mice were inter-crossed to obtain generations G2 and G3, as telomeres are known to shorten with subsequent generations. The TCL1+ mTerc-/- mice from the generations G1 (N=14), G2 (N=33) and G3 (N=26), including TCL1+ (N=34), wildtype (WT, N=18) and mTerc-/- G1 (N=4), G2 (N=5) and G3 (N=13) as controls were initially analyzed for disease burden in peripheral blood (PB) by bleeding at an interval of 4 weeks, starting from 12 weeks and the percentage of CD19+ CD5+ cells was estimated by FACS. No difference in disease onset or progression was observed between the TCL1+ mTerc-/- G1, G2 and G3 in comparison toTCL1+ mice (Fig. 1a). Similarly, analysis of survival showed no significant difference between the TCL1+ mTerc-/- G1 (N=14), G2 (N=33) and G3 (N=26) mice, compared to TCL1+ (N=34) (median: 53, 55, 52 weeks vs. 50.5 weeks, Fig. 1b). Spleen and liver weights in the TCL1+ mTerc-/- G1 (N=12), G2 (N=33) and G3 (N=26) mice were highly variable (spleen: 0.1g to 3.5g, liver: 0.1g to 8.0g) as in the TCL1+ (N=27, spleen: 0.3g to 5.0g, liver: 1.7g to 7.4g) mice but no significant difference in spleen (Fig. 1d) and liver weights was observed between the subgroups. Interestingly, spleen weights were associated with survival only in the TCL1+ mice, with larger spleens associated with worse survival (48.5 vs. 57.5 weeks, P=0.091). Since no difference in disease characteristics was observed, it was verified using Q-PCR, if telomere lengths vary in the tumors from the different subgroups. Telomere lengths of CLL cells from the spleen were significantly shorter (Fig. 1c) in the G1 (median: 20.5kb, P=0.0002), G2 (median: 18.5kb, P=0.0016) and G3 (median: 13.2kb, P<0.0001) compared to TCL1+ (median: 28.7kb). The absence of correlation of telomere length with survival in the murine CLL models with telomere dysfunction may indicate that a critical telomere length in the tumor is yet to be reached to elicit genetic alterations and clonal selection. Additionally, the G3 mTerc-/- microenvironment is known to restrict B and T lymphopoiesis and thus might influence CLL cell proliferation, masking disease aggressiveness in the TCL1+ mTerc-/- G3 mice. To overcome the influence of mTerc-/- microenvironment, CLL cells obtained from spleens of TCL1+ and TCL1+ mTerc-/- G3 mice were transferred into syngeneic C57Bl6 mice. Briefly, 20 million cells were intravenously injected into the tail vein and disease was monitored by analysis of CD19+ CD5+ cells in PB, once every 4 weeks. Early follow up of 8 weeks clearly show a trend towards increase in CLL cells in PB of mice transferred with TCL1+ mTerc-/- G3 tumors compared to those with TCL1+ tumors (median tumor load: 15.75% vs. 6.1%, P=0.0553). Longer follow up of the experiment is ongoing. In summary, the TCL1+ mTerc-/- mice across the generations G1, G2 and G3 showed no difference in disease onset, progression, disease burden and survival in comparison to TCL1+ mice. The absence of increased disease manifestation in the TCL1+ mTerc-/- may be attributed to the microenvironmental influence on lymphopoiesis, as syngeneic transfer of CLL from TCL1+ mTerc-/- G3 mice showed an increase in tumor load compared to that of TCL1+ tumors, indicating a contribution of telomere shortening to disease aggressiveness in CLL. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals A Clinical Comparison of Home-Based and Hospital-Based Exercise Programs Following Arthroscopic Capsulolabral Repair for Anterior Shoulder Instability

2020 ◽  
Vol 29 (6) ◽  
pp. 777-782
Author(s):  
İlker Eren ◽  
Nazan Canbulat ◽  
Ata Can Atalar ◽  
Şule Meral Eren ◽  
Ayla Uçak ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Shoulder Instability ◽  
Controlled Trial ◽  
Wilcoxon Test ◽  
Anterior Shoulder Instability ◽  
Controlled Clinical Trial ◽  
Rehabilitation Programs ◽  
Home Based ◽  
Significant Difference

Context: Ideal rehabilitation method following arthroscopic capsulolabral repair surgery for anterior shoulder instability has not been proven yet. Although rapid or slow protocols were compared previously, home- or hospital-based protocols were not questioned before. Objective: The aim of this prospective unrandomized controlled clinical trial is to compare the clinical outcomes of home-based and hospital-based rehabilitation programs following arthroscopic Bankart repair. Design: Nonrandomized controlled trial. Setting: Orthopedics and physical therapy units of a single institution. Patients: Fifty-four patients (49 males and 5 females) with an average age of 30.5 (9.1) years, who underwent arthroscopic capsulolabral repair and met the inclusion criteria, with at least 1-year follow-up were allocated into 2 groups: home-based (n = 33) and hospital-based (n = 21) groups. Interventions: Both groups received identical rehabilitation programs. Patients in the home-based group were called for follow-up every 3 weeks. Patients in the hospital-based group admitted for therapy every other day for a total of 6 to 8 weeks. Both groups were followed identically after the eighth week and the rehabilitation program continued for 6 months. Main Outcome Measures: Clinical outcomes were assessed using Disabilities of Arm Shoulder Hand, Constant, and Rowe scores. Mann–Whitney U test was used to compare the results in both groups. Wilcoxon test was used for determining the progress in each group. Results: Groups were age and gender matched (P = .61, P = .69). Average number of treatment sessions was 13.8 (7.3) for patients in the hospital-based group. Preoperative Disabilities of Arm Shoulder Hand (27.46 [11.81] vs 32.53 [16.42], P = .22), Constant (58.23 [14.23] vs 54.17 [10.46], P = .13), and Rowe (51.72 [15.36] vs 43.81 [19.16], P = .12) scores were similar between groups. Postoperative scores at sixth month were significantly improved in each group (P = .001, P = .001, and P = .001). No significant difference was observed between 2 groups regarding clinical scores in any time point. Conclusions: We have, therefore, concluded that a controlled home-based exercise program is as effective as hospital-based rehabilitation following arthroscopic capsulolabral repair for anterior shoulder instability.

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