Risk Factors For Myelodysplastic Syndromes Research Articles

Personal history of autoimmune disease and other medical conditions and risk of myelodysplastic syndromes

BackgroundAutoimmune diseases and hematopoietic malignancies are known to cluster within individuals, suggesting intertwined etiologies. A limited number of studies have evaluated pre-existing medical conditions as risk factors for myelodysplastic syndromes (MDS). We evaluated associations between autoimmune disease and other medical conditions and risk of MDS. MethodsCases were identified through the Minnesota Cancer Reporting System. Controls were identified through the Minnesota State driver’s license/identification card list. History of autoimmune disease and other medical conditions was based on self-report; proxy interviews were not conducted. Unconditional logistic regression was used to calculate adjusted odds ratios (aORs) and 95% confidence intervals (CI). ResultsWe included 395 cases and 694 controls. Cases were significantly more likely to report a diagnosis of any autoimmune disease when compared with controls (aOR=1.41, 95% CI: 1.05–1.89) after adjustment for age, sex, education, NSAID use, exposure to benzene and body mass index. When we evaluated specific autoimmune conditions, a statistically significant association was observed for hypothyroidism (aOR=2.16, 95% CI: 1.39–3.34) and odds ratios were elevated for inflammatory bowel disease (aOR=1.75) and systemic lupus erythematosus (SLE; aOR=3.65), although these associations did not reach statistical significance. Presence of an autoimmune condition did not impact overall survival (p = 0.91). ConclusionOur results validate previous findings of an association between autoimmune disease and MDS. Further studies are required to determine whether this association is due to shared etiology, treatment for autoimmune diseases, or altered immune surveillance or bone marrow damage caused by the autoimmune condition.

Mutational Signatures Associated with Intensity and Duration of Smoking in Myelodysplastic Syndromes (MDS)

Background:MDS pathogenesis is a multi-step molecular process resulting from somatic mutations acquired over time. Smoking is a known risk factor for MDS which may accelerate this process. To further investigate the contribution of tobacco use in MDS development, we studied the association between smoking and specific genomic alterations in MDS patients (pts).Methods: MDS and CMML pts diagnosed between 1996 and 2016 with both smoking histories and sequencing data were included. The Center for Disease Control definition defined current, ex- and never smokers, the latter defined as pts with zero smoking duration/packs per day (PPD). Next generation targeted sequencing was performed for a panel of 60 genes known to be commonly mutated in myeloid malignancies. Fisher's exact test and Wilcoxon's test compared proportions and medians, respectively. Poisson regression modeled total numbers of mutations per pt. The probability of a mutation in a particular gene was modeled using conditional logistic regression. Adjustment was done for both sex and age, fits were stratified using age cut points of 0, 40, 50, 60, 65, 70, 75, 80, 85 and 90 years (y). Odds ratios (OR) were found as exponentials of gene status coefficients of such fits.Results: In 672 pts, the median age at diagnosis was 68y (range, 20-103), for pt characteristics, see Table 1. Median OS 34 mo (95% CI 30-39) and median follow-up time was 21.5 mo (IQR, 10-45). Median tobacco exposures were 30 pack-years (py) in current smokers (range, 6-80) and 25 in ex-smokers (range, 0.3-175), P=.2. More men than women ever smoked (74% v 45%; P <.0001). Longer duration of smoking associated with higher IPSS-R categories (P=.012) and cytogenetic risk scores, P=.037. Most pts (502, 75%) had at least one mutation; 23% had a single gene mutation, 19% had 2, 15% had 3, and 18% had >3. The most frequently mutated genes were TET2 17%, ASXL1 16%, SRSF2 14%, SF3B1 12%, DNMT3A 10%, RUNX1 9%, STAG2 9%, and TP53 7%.Poisson regression analysis was used to assess the impact of smoking duration (y) or PPD on mutation acquisition. A positive correlation of greater smoking intensity (> 2 PPD v <0.5, relative increase (RI) =1.46, P=.011) and longer duration of smoking (>40y v <10, RI = 1.31, P=.011) was seen with increased number of mutations [Figure 1].Impact of duration of smoking was evaluated using logistic regression. Duration of smoking >40y v <1 was significantly associated with the following molecular abnormalities: FLT3 (P= .036), EZH2/ del7 (P=.038) and NRAS (P=.046). Comparing 20-40y v <1 yielded SETBP1 (P=.005), DNMT3A (P=.010) and EZH2 /del7 (P=.036). Comparing 10-20y v <1 yielded STAG2 (P=.039) and NOTCH1 (P=.046). Finally, comparing durations of 1-10y v <1 yielded PHF6 (P=.016). OR per mutation, see Table 2.Focusing on intensity of smoking, >2 PPD v <0.5 was significantly associated with higher rates of mutations in FLT3 (P=.013), EZH2 /del7 (P=.024), IDH1 (P=.041), and NPM1 (P=.044). Even low intensity smoking, comparing 0.5-1 PPD v <0.5, was significantly associated with mutations in SETBP1 (P=.002), DDX54 (P=.042) and DNMT3A (P=.046). For the combination of smoking duration and intensity, >40py v <10 was associated with IDH1 mutation (P=.046), while 20-30 py v <10 significantly associated with RAD21 (P=. 016), DDX54 (P=.018), SRSF2 (P=.041), del7/ EZH2 (P=.042), and NF1 (P=.045) mutations. Comparing 1-10py v <1, significant associations were found for IDH1 (P=.004), PRPF8 (P=.011), SETBP1 (P=.022), ETV6 (P= .040) and TET2 (P=. 047)mutations [Table 2]. Analyses were repeated after excluding CMML and MDS/MPN pts to control for the common genomic phenotype seen in these disorders, with identical results.Conclusions: Tobacco smoking predisposes to either acquisition or selection of distinct somatic mutational patterns from those seen in “spontaneous/non-tobacco exposed” MDS. EZH2/ del7 abnormalitiesassociated with longer durations and heavier smoking patterns, while SETBP1 mutation associated with lighter smoking for prolonged durations. Lesions associated with light smoking for years may be related to chronic inflammatory changes, whereas those associated with higher intensity may reflect direct DNA damage. Validation of these findings warrants earlier sequencing in pts with pre-MDS conditions such as clonal hematopoiesis of indeterminate potential to better identify the onset of somatic mutations and their role in MDS pathogenesis. [Display omitted] DisclosuresAdvani:Takeda/ Millenium: Research Funding; Pfizer: Consultancy. Gerds:CTI BioPharma: Consultancy; Incyte: Consultancy. Maciejewski:Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fees; Apellis Pharmaceuticals: Consultancy; Ra Pharma: Consultancy. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees.

Distribution of Natural Killer Cell in Patients with Newly Diagnosed Myelodysplastic Syndromes and Its Correlation with Prognosis

To investigate the distribution of peripheral blood lymphocytes and natural killer (NK) cells, and its influence on the prognosis of patients with myelodysplastic syndromes (MDS). The lymphocytes proportion, absolute lymphocyte counts (ALC), NK cell proportion and absolute NK cell counts (ANKC) as well as the related data of 95 MDS patients diagnosed between 2013 and 2017 analyzed retrospectively. The correlation of ALC and ANKC with prognosis was also analyzed. As compared with low ALC patients, MDS patients with ALC≥0.885×109/L had a higher overall response rate (66.7% vs 35.8%) (P＜0.01). The ALC of effective patients after treatment significatitly increased in compaison of ALC at diagnosis. Multivariate analysis indicated that patients with ALC≥0.885×109/L had long overall survival (OS) time in comparison with patients with low level (16.4 vs 12.4 months) (P＜0.05). The OS time of patients with ANKC≥0.110×109/L was shorter in comparison with patients with low level (10.9 vs 16.3 months) (P＜0.01). Otherwise, blast, cytogenetic risks and treatment response were also independent risk factors of MDS (P＜0.05). Revised International Prognostic Scoring System (IPSS-R) combined with ANKC could improve predictive accuracy of IPSS-R alone (AUC 0.718 vs 0.674) (P＜0.05). Lymphocytes and NK cells are important for the prognosis evaluation of MDS patients.

History of Autoimmune Disease Is Associated with Increased Risk for Myelodysplastic Syndromes

Background With the exception of therapy related MDS due to treatment with alkylating agents and/or radiation or with a topoisomerase II inhibitor, little is known about the etiology of myelodysplastic syndromes (MDS). A few studies have evaluated pre-existing medical conditions as risk factors for MDS, with evidence suggesting that autoimmune disease is associated with an increased risk of MDS. Here, we evaluated associations between history of autoimmune disease, overall and by individual disease subtype, and risk of MDS in a population-based case control study. Methods MDS cases were identified by rapid case ascertainment through the population-based Minnesota Cancer Surveillance System (MCSS). Participants were recruited if they were diagnosed with MDS between April 1, 2010 and October 31, 2014. Eligibility criteria included residence in Minnesota, age at diagnosis between 20 and 85 years, and ability to understand English or Spanish. Centralized pathology and cytogenetics review were conducted to confirm diagnosis and classify by subtypes. Controls were identified through the Minnesota State driver's license/identification card list. History of autoimmune disease was reported using a self-administered questionnaire; proxy interviews were not conducted. Unconditional logistic regression with adjustment for age, sex and confounders (education, NSAID use, benzene exposure, BMI) was used to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CI) for autoimmune disease and MDS. Results A total of 399 cases with a confirmed diagnosis of MDS and 1399 controls were included. Cases were significantly more likely to report a diagnosis of any autoimmune disease when compared with controls (OR=1.49, 95% CI 1.13-1.97). As illustrated in Figure 1, specific associations were observed for hypothyroidism (OR=2.07, 95% CI 1.39-3.08), ulcerative colitis (OR=2.26, 95% CI 1.09-4.69), Crohn's disease (OR=3.88, 95% CI 1.23-12.2), and systemic lupus erythematosus (SLE; OR=7.52, 95% CI 1.98-28.6). Autoimmune conditions were more commonly reported in both female cases and female controls when compared with males; however, associations for hypothyroidism and ulcerative colitis were significantly associated with MDS in males in an analysis stratified by sex. Associations between autoimmune disease and MDS remained statistically significant after exclusion of therapy-related MDS cases. Discussion Our results validate previous findings of an association between autoimmune disease and MDS risk from population-based registry studies and case-control studies. In addition, our results provide additional evidence to suggest that this association is largely driven by hypothyroidism, inflammatory bowel disease, and SLE. This increased MDS risk following a diagnosis for an autoimmune condition is hypothesized to be due to shared genetic or environmental risk factors, treatment for autoimmune diseases, altered immune surveillance or damage to the bone marrow caused by the autoimmune condition. Further studies are required to confirm which of these is the most plausible explanation. Disclosures No relevant conflicts of interest to declare.

Medical Conditions and Modifiable Risk Factors for Myelodysplastic Syndrome: A Systematic Review.

The aim of this systematic review was to evaluate medical conditions and modifiable risk factors for myelodysplastic syndromes (MDS) using the 2001 or 2008 World Health Organization (WHO) diagnostic criteria. PubMed, MEDLINE, and Scopus databases were searched for studies published between January 2001 and August 2017. Study characteristics and findings were abstracted for each article. Thirteen articles (4 cohort, 9 case-control) met the inclusion criteria. Smoking and alcohol use were each evaluated as potential MDS risk factors in four studies. Body mass index and anemia were each evaluated in two studies. Other potential risk factors evaluated in single studies included physical activity, dietary intake (tea, isoflavones, meat, fruit, or vegetables), history of allergies, autoimmune disorders and community-acquired infections, and use of antituberculosis drugs, traditional Chinese medicines, or hair dyes. Higher BMI, smoking, a history of autoimmune disorders, community-acquired infections, history of anemia, and use of antituberculosis drugs were associated with higher risk of MDS. Vigorous physical activity and tea and dietary isoflavone intake were associated with lower MDS risk. These findings suggest no association between the other factors and risk of MDS. Research on risk factors for MDS is limited, and further research in larger studies is needed.

Occupational, dietary, and other risk factors for myelodysplastic syndromes in Western Greece

ABSTRACTPurpose: We have observed an increasing incidence of myelodysplastic syndromes (MDS) in the geographic area of Western Greece during the past two decades. The objective of this study was to investigate potential risk factors for the manifestation of MDS in this area of Greece.Methods: A hospital-based case–control study was conducted in the public hospitals of the region. Participants were interviewed based on a questionnaire regarding demographics, occupational exposures, smoking, alcohol consumption, dietary, and domestic factors.Results: A total of 228 individuals (126 cases, 102 controls) were recruited in this study. Univariate analysis showed that risk of MDS was associated with a family history of hematologic malignancy or solid tumor, exposure to pesticides, insecticides, herbicides, increased weekly intake of meat and eggs, and increased alcohol intake, whereas fruit intake had a protective effect. Analysis by pesticide ingredient showed a weak association of exposure to paraquat and glyphosate with the occurrence of MDS. Multivariate analysis showed that independent risk factors for the manifestation of MDS were family history of solid tumor (OR 2.47, 95% CI 1.32–4.65), meat intake for ≥5 days/week (OR 2.67, 95% CI 1.05–6.80) and exposure to pesticides (OR 3.25, 95% CI 1.73–6.11).Conclusions: Exposure to pesticides is a major risk factor of MDS in Western Greece. Family history of solid tumor and increased meat intake also appear to play a role in the pathogenesis of MDS. Public health authorities should implement policies to advise and protect farmers from the harmful effects of agrochemicals. Emphasis should also be given to health promotion advice including healthy eating.

Abstract 3427: Chemical exposures and risk of acute myeloid leukemia and myelodysplastic syndromes in a population-based study

Abstract Background Myelodysplastic syndromes (MDS) are a group of clonal hematologic disorders that result in ineffective hematopoiesis. Individuals with MDS have a high risk of progressing to leukemia, with approximately 30% expected to develop acute myeloid leukemia (AML). Benzene exposure is one of the few well-established risk factors for AML, and recent studies suggest it is also a risk factor for MDS. Exposure to other occupational and residential chemicals has been inconsistently associated with hematologic malignancies. In this analysis, we evaluated occupational and residential chemical exposures as risk factors for AML and MDS using population-based data. Methods AML and MDS cases were identified by rapid case ascertainment through the Minnesota Cancer Surveillance System (MCSS). Centralized pathology and cytogenetics reviews were conducted to confirm diagnosis and classify by subtypes. Controls were identified through the Minnesota State driver's license/identification card list. Chemical exposures were measured by self-report and included occupational and residential exposure to a variety of chemicals. Unconditional logistic regression with adjustment for age, sex, previous cancer treatment, income, and farm or rural residence was used to calculate crude and adjusted odds ratios (ORs) and 95% confidence intervals (CI). Smoking, obesity and physical activity were considered as potential confounders but did not change effect estimates by 10% or more. Results We included 265 MDS cases, 420 AML cases, and 1388 controls in this analysis. As expected, we observed significant associations between benzene and both MDS and AML (OR = 1.77, 95% CI 1.17, 2.67 and OR = 2.03, 95% CI 1.45, 2.83, respectively). Exposure to vinyl chlorides was associated with MDS (OR = 2.25, 95% CI 1.32, 3.81) but not with AML (OR = 1.36, 95% CI 0.83, 2.21). Exposure to fertilizers (OR = 1.70, 95% CI 1.11, 2.59), soot (OR = 2.64, 95% CI 1.59, 4.39), creosote (OR = 1.95, 95% CI 1.08, 3.51), inks, dyes and tanning solutions (OR = 1.63, 95% 1.02, 2.60), and coal dust (2.64, 95% CI 1.30, 5.39) were associated with AML, while no association was seen between any of these exposures and MDS (range ORs = 0.78-1.25). No significant associations were observed for occupational pesticide exposures in either group. Discussion These data confirm the importance of benzene as a risk factor for myeloid malignancy and provide risk estimates in a population-based sample. A number of other significant associations with occupational and residential chemicals were observed for AML; however, all exposures were reported by only a small percentage of cases (≤10%). While chemical exposures play a clear role in the etiology of myeloid malignancy, these exposures do not account for the majority of cases. Citation Format: Jenny N. Poynter, Michaela Richardson, Michelle Roesler, Cindy K. Blair, Betsy Hirsch, Phuong Nguyen, Adina Cioc, James R. Cerhan, Erica Warlick. Chemical exposures and risk of acute myeloid leukemia and myelodysplastic syndromes in a population-based study. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3427.

Secondary Myeloid Neoplasms in Older Women with Breast Cancer after Radiotherapy: A Population-Based Study

BACKGROUND: Chemotherapy and combined chemo-radiotherapy are well-documented risk factors for myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), collectively referred to in this setting as therapy-related myeloid neoplasms (t-MN). While single-modality radiotherapy post-lumpectomy has been shown to reduce local recurrence among breast cancer patients, data regarding the impact on development of t-MN are limited and inconsistent.METHODS: We conducted a retrospective cohort study of elderly female breast cancer patients (aged 67-94 years at diagnosis) who were diagnosed with in situ or stage 1-3 breast cancer between 1/1/2004 and 12/31/2011 using the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER)-Medicare linked database. Eligibility criteria included 1) enrollment in Medicare Parts A and B continuously through death or end of study (12/31/2013); 2) underwent surgery for breast cancer within 9 months of diagnosis; and 3) were not diagnosed with other neoplasms prior to breast cancer diagnosis. Delivery of radiation therapy was ascertained using the Healthcare Common Procedural Coding System codes. In order to be considered a recipient of radiotherapy, the patient had to receive radiotherapy within 9 months of diagnosis and had any treatment delivery code for brachytherapy or ≥ 4 treatment delivery codes for external bream radiotherapy. Competing-risk analysis was used to assess the risk of developing t-MN in radiotherapy-treated patients compared to those treated with surgery alone. Patients were censored at the time of receiving chemotherapy or at development of another malignancy (aside of t-MN) during follow-up. Competing-risk analysis was used to assess the risk of developing secondary MN women who received radiation therapy compared to those who did not. These models included adjustment for breast cancer diagnosis age and year, number of comorbidities, anemia, functional status prior to breast cancer diagnosis and breast cancer stage.RESULTS: A total of 63,543 patients were included in the study. Median follow-up for all participants was 48 months. A total of 32,809 patients (51.6%) received radiotherapy post-surgery while 30,734 patients (48.4%) were not treated with radiotherapy post-surgery. Patients who received radiotherapy had significantly better overall survival than those who did not (median overall survival [OS] 107 vs. 89 months, p<0.001). During follow-up, a total of 167 patients were diagnosed with MDS or AML (89 cases among those who received radiotherapy and 78 among those who did not receive radiotherapy). The median time to develop MDS/AML was 24 months. In the unadjusted model, there was no significantly increased risk of subsequent AML/MDS among breast cancer patients who received single-modality radiotherapy compared to those who underwent surgery alone (hazard ratio [HR] = 1.11, 95% confidence interval [CI]: 0.82-1.51, p=0.49). Similarly, no significant difference in subsequent MDS/AML according to receipt of radiotherapy was observed in the adjusted analysis (HR = 1.16, 95% CI: 0.84-1.59, p=0.36).CONCLUSIONS: Older patients with early breast cancer who were treated with single-modality radiotherapy post-surgery did not have a higher risk of subsequent MDS/AML compared to patients who did not receive radiotherapy, and the overall rate of MN was low.While additional studies with a longer duration of follow-up are warranted, these results suggest that the single-modality radiotherapy administered in the contemporary management of early breast cancer is not a risk factor for t-MN in this population. DisclosuresYu:21st-Century Oncology LLC: Research Funding. Gore:Celgene: Consultancy, Honoraria, Research Funding. Gross:Johnson and Johnson: Research Funding; Medtronic: Research Funding; 21st-Century Oncology LLC: Research Funding. Ma:Celgene Corp: Consultancy; Incyte Corp: Consultancy. Davidoff:Celgene: Consultancy, Research Funding.

Pesticide exposure as a risk factor for myelodysplastic syndromes: a meta-analysis based on 1,942 cases and 5,359 controls.

ObjectivePesticide exposure has been linked to increased risk of cancer at several sites, but its association with risk of myelodysplastic syndromes (MDS) is still unclear. A meta-analysis of studies published through April, 2014 was performed to investigate the association of pesticide exposure with the risk of MDS.MethodsStudies were identified by searching the Web of Science, Cochrane Library and PubMed databases. Summary odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated using random- or fixed-effect models.ResultsThis meta-analysis included 11 case-control studies, all of which demonstrated a correlation between pesticide exposure and a statistically significant increased risk of MDS (OR = 1.95, 95% CI 1.23–3.09). In subgroup analyses, patients with pesticide exposure had increased risk of developing MDS if they were living in the Europe or Asia and had refractory anemia (RA) or RA with ringed sideroblasts (RARS). Moreover, in the analysis by specific pesticides, increased risk was associated with exposure to insecticides (OR = 1.71, 95% CI 1.22–2.40) but not exposure to herbicides or fungicides.ConclusionThis meta-analysis supports the hypothesis that exposure to pesticides increases the risk of developing MDS. Further prospective cohort studies are warranted to verify the association and guide clinical practice in MDS prevention.

Alcohol consumption and risk of myelodysplastic syndromes: A meta-analysis of epidemiological studies.

Previous studies on the association between alcohol intake and the risk of myelodysplastic syndromes (MDS) have been inconclusive. We conducted a meta-analysis to evaluate alcohol intake as a risk factor for MDS. We performed a systematic literature search of articles published before March, 2014 using Web of Science, PubMed and the Cochrane Library. Two evaluators independently selected and reviewed studies based on predetermined selection criteria. The fixed- or random-effects models were used to summarize the estimates of odds ratios (ORs) with 95% confidence intervals (CIs). A total of 9 studies (8 case-control and 1 cohort) met the inclusion criteria of this meta-analysis. No significant association was observed between alcohol consumption and MDS when comparing drinkers to non-drinkers (OR=1.16, 95% CI: 0.88-1.53) or between subgroups stratified by alcohol history, gender, ethnicity, study design, source of patients or MDS subtypes. However, the data indicated a stronger association of alcohol with MDS in individuals who consumed ≥10 g/day (OR=1.55, 95% CI: 1.08-2.21) vs. those who consumed <10 g/day (OR=1.09, 95% CI: 0.78-1.53). This meta-analysis suggests that alcohol intake may increase the risk of MDS in a dose-dependent manner. However, additional well-designed, prospective cohort studies are required to verify these findings and identify other risk factors associated with MDS.

P-260 Exposure to pesticides is a major risk factor for myelodysplastic syndromes (MDS) in Southwestern Greece

P-260 Exposure to pesticides is a major risk factor for myelodysplastic syndromes (MDS) in Southwestern Greece

P-120 Risk factors in myelodysplastic syndromes (MDS): A single centre retrospective study

P-120 Risk factors in myelodysplastic syndromes (MDS): A single centre retrospective study

DNA repair gene variants are associated with an increased risk of myelodysplastic syndromes in a Czech population

BackgroundInteractions between genetic variants and risk factors in myelodysplastic syndromes are poorly understood. In this case–control study, we analyzed 1 421 single nucleotide polymorphisms in 408 genes involved in cancer-related pathways in 198 patients and 292 controls.MethodsThe Illumina SNP Cancer Panel was used for genotyping of samples. The chi-squared, p-values, odds ratios and upper and lower limits of the 95% confidence interval were calculated for all the SNPs that passed the quality control filtering.ResultsGene-based analysis showed nine candidate single nucleotide polymorphisms significantly associated with the disease susceptibility (q-value < 0.05). Four of these polymorphisms were located in oxidative damage/DNA repair genes (LIG1, RAD52, MSH3 and GPX3), which may play important roles in the pathobiology of myelodysplastic syndromes. Two of nine candidate polymorphisms were located in transmembrane transporters (ABCB1 and SLC4A2), contributing to individual variability in drug responses and patient prognoses. Moreover, the variations in the ROS1 and STK6 genes were associated with the overall survival of patients.ConclusionsOur association study identified genetic variants in Czech population that may serve as potential markers for myelodysplastic syndromes.

Myelodysplastic Syndrome: An Egyptian Experience

Background: Myelodysplastic syndromes (MDS) incidence is unclear because of historical lack of populationbased registration and possibly because of under diagnosis. Purpose: To present some retrospective data on the epidemiology of Myelodysplastic syndrome (MDS) in Egypt, as reflected by a single centre which is the largest tertiary referral center of Haematology in Egypt. Patients and Methods: Patients diagnosed with MDS and referred to Clinical Haematology unit of Internal Medicine Department Cairo University, Egypt between 2007-2010 were identified. Complete demographic and clinical data, laboratory results, treatment modalities were collected and analyzed. Results: Sixty nine patients with MDS were identified. Thirty nine (57%) females, thirty (43%) male subjects. Mean age was 55 years. Nine (13%) patients were positive for HCV. Mean ferretin level was 844 ng/ml and mean blood transfusion units were 12 units. Twelve (17%) patients were less than 40 years, 4 (5%) of them had RAEB. There were a strong correlation between ferretin and ALT (alanine transaminase) (r=0.415 P:0.002), ferretin and blood units (r=0.26 P:0.046) and negative correlation between ferretin and age (r=-0.27 p:0.03). Forty eight (70%) patients were from rural areas. Twenty five (36%) males were cigarette smokers. None of the females patients were smokers. Conclusion: Mean age of presentation of MDS in Egypt is lower than developed countries. Pollution of water and use of insecticides and smoking are high risk factors for MDS among Egyptians while hair dyes and alcohol couldn’t be assessed due to cultural reasons. HCV role in pathogenesis of MDS still to be determined. Iron overload is a permanent feature of MDS. The higher mean ALT and ferretin levels and their positive correlation reflect the impact of under treatment of those patients with iron chelation therapy on progression of liver disease.

141 A case-control study to investigate risk factors for myelodysplastic syndromes in Southwestern Greece

141 A case-control study to investigate risk factors for myelodysplastic syndromes in Southwestern Greece

Case–control study of risk factors of myelodysplastic syndromes according to World Health Organization classification in a Chinese population

Risk factors of mydelodysplastic syndromes (MDS) remain largely unknown. We conducted a hospital-based case-control study consisting of 403 newly diagnosed MDS patients according to World Health Organization classification and 806 individually gender and age-matched patient controls from 27 major hospitals in Shanghai, China, to examine relation of lifestyle, environmental, and occupational factors to risk of MDS. The study showed that all MDS (all subtypes combined) risk factors included anti tuberculosis drugs [odds ratio (OR)(adj) = 3.15; 95% confidence interval (CI) = 1.22-8.12] as an independent risk factor, benzene (OR(adj) = 3.73; 95% CI = 1.32-10.51), hair dye use (OR = 1.46; 95% CI = 1.03-2.07), new building and renovations (OR = 1.69; 95% CI = 1.11-2.00), pesticides (OR = 2.16; 95% CI = 1.22-3.82), and herbicides (OR = 5.33; 95% CI = 1.41-20.10) as relative risk factors. Risk factors of MDS subtype refractory cytopenia with multiple dysplasia (RCMD) were benzene (OR(adj) = 5.99; 95% CI = 1.19-30.16) and gasoline (OR(adj) = 11.44; 95% CI = 1.31-100.03) as independent risk factors, and traditional Chinese medicines (OR = 2.17; 95% CI = 1.15-4.07), pesticides (OR = 2.92; 95% CI = 1.37-6.25), and herbicides (OR = 12.00; 95% CI = 1.44-99.67) as relative risk factors. Smoking tobacco was significantly associated with refractory anemia with excess of blasts (RAEB) (OR(adj) = 2.43; 95% CI = 1.02-5.77). Education is shown as an independent protective factor against all MDS (OR(adj) = 0.90; 95% CI = 0.83-0.99) and RCMD (OR(adj) = 0.89; 95% CI = 0.79-0.99). These findings suggest that multiple modifiable behavioral, environmental, and occupational factors play a role in MDS etiology, and various MDS subtypes may have different susceptibility.

The search for better prognostic models in myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) are a group of heterogeneous bone marrow disorders characterized by a failure of hematopoiesis and an increased propensity for transformation to acute myeloid leukemia. Determining the prognosis of patients with MDS is essential for discerning the best therapy, which can vary from supportive care to allogeneic stem cell transplantation. The most widely used prognostic model in MDS is the International Prognostic Scoring System (IPSS), which estimates survival and risk of transformation to acute myeloid leukemia based on the percentage of blasts, karyotype, and number of cytopenias, but the IPSS has several limitations that preclude more widespread application. Over the past decade, several studies have reported on new prognostic factors for MDS, including transfusion dependency and DNA methylation abnormalities. More recently, two prognostic models for MDS that aim to overcome the limitations of the IPSS have been published. This review focuses on the most recent advances in this field, detailing current prognostic models and the more important risk factors in MDS.

13 Update of cytogenetic risk factors in MDS (Part II): a strategy to incorporate fluorescence in situ hybridization (FISH) and “FISH on a Chip” (aCGH) results in future clinical trials for the myelodysplastic syndromes (MDS)

13 Update of cytogenetic risk factors in MDS (Part II): a strategy to incorporate fluorescence in situ hybridization (FISH) and “FISH on a Chip” (aCGH) results in future clinical trials for the myelodysplastic syndromes (MDS)

Smoking as a risk factor for myelodysplastic syndromes and acute myeloid leukemia and its relation to cytogenetic findings: A case–control study

In this case–control study, interview data on smoking habits were available for 179 de novo cases (116 with cytogenetic data) of acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). Smoking habits were compared with a pooled set of population controls and hospital controls (diagnosed with malignant melanoma). Each pack-year of smoking increased the risk of MDS with 1.3% (95% CI 0.1–2.6%), corresponding to an estimated excess risk of 71% (95% CI 3–180%) for 40 pack-years. Associations between smoking and the specific aberrations -5/5q-, -7/7q-, and +8 in AML and MDS were indicated but the estimates were imprecise.

Short Telomere Length as a Risk Factor for Myelodysplastic Syndromes: A Case-Control Study

BACKGROUND: Predisposition to myelodysplastic syndromes (MDS) may arise from accelerated cellular senescence of bone marrow stem cells, a hallmark of the aging process. Proliferative senescence can by triggered by critically shortened telomeres, and previous studies have reported shorter telomere length in myeloid cells of MDS patients as compared to healthy controls. Because myeloid cells are progeny of the malignant clone, it is unclear whether telomere length plays a pathogenetic role in the development of MDS or represents soley a disease specific phenotype. To investigate the role of telomere length in MDS susceptibility, we conducted a case-control study of 65 newly diagnosed MDS patients and 63 controls.METHODS: Cases of MDS were recruited at the Moffitt Cancer Center (n=58) and through a study advertisement posted on the Myelodysplastic Syndromes Foundation website (n=7). MDS patients were eligible to participate if they were age 18 or older, had received no MDS treatment other than growth factors, and had no prior history of cancer. All MDS diagnoses were histologically confirmed and characterized by WHO and IPSS category. Controls were visitors who accompanied patients and were frequency-matched to MDS cases based on sex and age within 10 years. Eligible controls were not biologically related to the cases and did not have a history of cancer. All study participants completed a risk factor questionnaire, which included history of occupational exposures. DNA was extracted from heparinized whole blood samples, and telomere lengths were measured using real-time PCR. The ratio of telomere repeat copy number (T) to the copy number of a single-copy gene (beta-actin) (S) was determined using standard curves, where the T/S ratio is proportional to the cell's average telomere length. In a subset of participants (n=18 cases and 15 controls), telomere length was also measured in CD15+ and CD19+ cells by quantitative fluorescence in situ hybridization assays using flow cytometry (flow-FISH). Peptide nucleic acid (PNA)-telomere probe binding in a population of cells with long telomeres (1301 cells) was used as both a reference internal standard in each flow-FISH assay and for quantification. In addition, a polymorphism in the telomerase reverse transcriptase gene (hTERT) previously shown to be associated with aplastic anemia (A1062T) was investigated using a Taqman allele differentiation assay. Telomere lengths were compared between MDS cases and controls using logistic regression with adjustment for age. To investigate potential determinants of telomere length among the MDS cases, analysis of covariance with age adjustment was used to compare telomere lengths by hTERT genotype and past occupational exposures.RESULTS: Telomere lengths in whole blood were significantly shorter among MDS cases [mean (SD) T/S ratio for cases= 3.9 (2.3))] as compared to controls [mean (SD)=5.6 (4.6)] (p=0.01). Among MDS cases, telomere lengths in whole blood differed by MDS subtype, ranging from a mean T/S ratio of 2.2 in patients with refractory anemia [n=7] to 4.3 in patients with refractory anemia with ringed sideroblasts [n=9] (p=0.13). The A1062T polymorphism was present in 6% of cases versus 3% of controls (p=0.68) and was not associated with telomere length in either cases or controls. MDS cases were more likely than controls to report past occupational exposures to paints (p=0.11), insecticides (p=0.06) and organophosphates (p=0.06), and telomere lengths were shorter among those exposed to these substances than those who were not (p=0.10). Flow-FISH analysis showed that MDS cases had shorter telomere lengths in both CD15+ neutrophils (mean (SD) fluorescence units relative to 1301 = 10.0 (1.2) for cases and 11.5 (1.4) for controls; p=0.009) and CD19+ lymphocytes (cases = 11.7 (1.7), controls= 12.6 (1.4); p=0.15). Among MDS cases, telomere lengths in CD15+ and CD19+ cells were significantly correlated (Spearman correlation coefficient = 0.50, p=0.03).CONCLUSION: Our findings of reduced age-adjusted telomere length in both neutrophils and B-cells of MDS suggests that accelerated telomere shortening may be a marker of genetic susceptibility to MDS.