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Abstract

The myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic disorders. This study aims to advance the use of spatial modeling in disease etiology and monitoring based on reports on a large population (n=984) of MDS patients diagnosed in the Eastern United States. The spatial MDS clustering was analyzed using SaTScan, and patient clinical characteristics were analyzed using logistic regression and Cox hazards models adjusting for covariates. One main and five secondary spatial clusters (p-value <10(-17)-10(-7)) were identified. Patients living in high vs. low MDS incidence clusters tended to be older (ORadj= 1.04 [1.004, 1.07]) and smokers (ORadj=2.9 [1.1, 7.4]). Mortality were associated with hemoglobin (HRadj=0.7 [0.5, 0.9]), neutrophils (HRadj=0.7 [0.6, 0.96]), platelets (HRadj=0.5 [0.4, 0.7]), and blast (HRadj=1.4 [1.1, 1.8]), but not clusters. The results suggest large geographic variations in MDS incidence rates. The biological aggressiveness of the disease is unlikely to be associated with its spatial distribution.

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... However, the median age at diagnosis in China is 49 years [36]. Similarly, in a recent attempt to generate more accurate hypotheses on MDS etiology, epidemiologists performed spatial clustering analysis to link clusters of MDS cases to specific areas [37,38]. Although it is a relatively new approach, this epidemiologic tool may allow a better definition of the role of personal, behavioral, and clinical factors in MDS etiology and outcome. ...
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Myelodysplastic syndromes (MDS) affect more than 30,000 patients in the USA per year, most of whom are elderly, and these diseases are associated with dismal prognoses. The main features of MDS are ineffective hematopoiesis and aberrant myeloid differentiation. Furthermore, MDS are heterogeneous, both clinically and molecularly. This heterogeneity and the frequent occurrence of age-related comorbidities make the management of these diseases challenging. In fact, there have been no new drug approvals for MDS in the USA in the last 9 years, and few currently available investigational drugs are likely to be approved in the near future. Novel targeted treatment based on better understanding of the pathogenesis of MDS is needed to maximize patient outcomes. Here, we discuss new insights into diagnostic accuracy, prognostic assessment, pathogenic mechanisms, and effective treatments for MDS.
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Article
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Article
BACKGROUND Myelodysplastic syndromes (MDS) appear to be underreported to cancer registries, with important implications for cancer and transfusion support service planning and delivery. Two population-based databases were linked to estimate MDS incidence more accurately.METHODS Data from the statewide Victorian Cancer Registry (VCR) and Victorian Admitted Episode Dataset (VAED, capturing all inpatient admissions), in Australia, were linked. Incidence rates were calculated based on VCR reported cases and using additional MDS cases identified in VAED. Differences between reported and nonreported cases were assessed. A multivariate capture-recapture method was used to estimate missed cases.RESULTSBetween 2003 and 2010, 2692 cases were reported to VCR and an additional 1562 cases were identified in VAED. Annual incidence rate for those aged 65 years and older based on VCR was 44 per 100,000 (95% confidence interval [CI] = 43-45 per 100,000) and 68 per 100,000 (95% CI = 67-70 per 100,000) using both data sets. Cases not reported to VCR were more likely to have had previous malignancies recorded in VAED (23% versus 19%, P = .003) and to require red cell transfusion (59% versus 54%, P = .003). Using the multivariate model, an estimated 1292 cases were missed by both data sources: the re-estimate was 5546 (95% CI = 5438-5655) MDS cases, with an annual incidence in those aged 65 or older of 103 per 100,000 (95% CI = 100-106).CONCLUSIONS This study reports a higher incidence of MDS using 2 data sources from a large and well-defined population than reported using cancer registry notifications alone. Cancer 2014. © 2014 American Cancer Society.
Article
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Myelodysplastic syndromes (MDS) prognosis is currently based solely on clinical parameters. The identification of additional factors associated with MDS outcome could be used to further improve the current scoring system such as the International Prognostic Scoring System (IPSS). The present study evaluates the role of epidemiological markers as predictors of survival for 365 adult de novo MDS patients. Multivariable Cox regression analysis was used to estimate overall survival. Median follow-up time was 22 months. At the time of last follow-up, 271 patients (74.3 %) had died. For all MDS patients, medium-high lifetime occupational agrochemical exposure (HR 1.85, CI 1.19-2.89) remained as an independent predictor of MDS survival. Stratified analysis by gender showed that ≥25 pack-years smoked (HR 1.44, CI 1.001-2.09) and medium-high lifetime occupational agrochemical exposure (HR 1.84, CI 1.15-2.97) were independent predictors of MDS survival in men, but not in women. For MDS patients stratified by IPSS categories, ≥25 pack-years smoked (HR 1.75, CI 1.005-3.06) was an independent predictor for intermediate 1 IPSS risk group only, and medium-high lifetime occupational agrochemical exposure was associated with increased mortality (HR 4.36, CI 1.20-15.8) in the high IPSS risk group. Smoking and lifetime occupational agrochemical exposure may play a role in MDS survival. Incorporating relevant epidemiological markers with known clinical predictors of outcome may help physician stratify patients and customize treatment strategies to improve the outcome of MDS.
Article
The myelodysplastic syndromes (MDS) are often diagnosed in outpatient clinics and may be under-reported to state cancer registries, which predominantly rely on hospital records and laboratory reports. We used a new method of cancer case capture to determine the rate of missed cases and estimate a more accurate incidence of MDS. Using a unique keyword algorithm, we queried all electronic pathology (E-path) reports sent to the state of Florida cancer registry in 2006 to identify potential MDS cases. A stratified, random sample of E-path reports was then reviewed to confirm diagnosis and assign MDS subtype. Characteristics were compared between captured and uncaptured MDS cases. 7111 E-path reports with MDS keyword hits were identified, of which only 18% linked to a registered MDS case, 47% linked to a different cancer, and 34% did not link with any record. Case review of a stratified, random sampling of 285 individuals led to the discovery that uncaptured cases made up 37.7% of the total true MDS cases in 2006. It is estimated that the true incidence of MDS is 5.3 individuals out of 100,000, compared to previous reports of 3.3 out of 100,000. Uncaptured MDS cases were younger and more likely to have information in the pathology report facilitating MDS subtype assignment. Only two-thirds of true MDS cases are captured in Florida using current case-finding mechanisms. Application of a keyword search strategy to identify cases among E-path reports is a feasible technique to improve MDS case ascertainment.
Article
Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic stem cell malignancies that represent a diagnostic challenge for pathologists. Accurate classification and prognostic scoring are essential to treating MDS. To understand factors that affect MDS management, a case-based survey was distributed to hematopathologists (n=53) and general pathologists (n=72) to identify perceived barriers, attitudes, and practices in MDS diagnosis. Results demonstrated confidence and practice gaps. Only 33% of general pathologists are confident in diagnosing MDS. Neither general pathologists nor hematopathologists are comfortable using the International Prognostic Scoring System to characterize risk. Thirty percent of general pathologists and 22% of hematopathologists would not include bone marrow aspirate and cytogenetics in initial testing of a neutropenic patient. Most practitioners tested appropriately for disease classification and prognosis; discrepancies were identified in testing to differentiate MDS from acute myeloid leukemia and testing in post treatment specimens. These results have implications in the management of MDS.
Article
Myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal hematopoietic stem cell malignancies with significant morbidity and high mortality. The incidence of MDS increases markedly with age, and the disease is most prevalent in individuals who are white and male. It is conservatively estimated that >10,000 new cases of MDS occur in the United States annually, and that ≥ 60,000 individuals with MDS currently reside in the country. With an aging population and an improving awareness of the disease, the documented disease burden is expected to escalate in the near future. Recent studies have identified new or inconsistent etiologic factors that warrant further research. Given the poor survival of individuals with MDS, it is important to identify prognostic factors to better risk-stratify patients for more effective treatment. The relevance of different comorbidities to MDS prognosis and the potential interaction between various comorbidities represents an interesting area of research.
Article
Aetiological factors of the myelodysplastic syndromes (MDS) are largely unknown, with the exception of alkylating agents, ionizing radiation and benzene. Some other risk factors have been suggested by the few epidemiological studies reported (solvents, ammonia, exhaust gases, metals, pesticides, alcohol). We performed a case–control study to assess the relationship between occupational or environmental factors and MDS. Two hundred and four patients with newly diagnosed MDS, and 204 sex- and age-matched controls were included. Medical history, demographic data, lifetime exposure and hobbies were obtained. Qualitative and quantitative exposure to chemical and physical hazards were evaluated with the patients and reviewed by a group of experts in occupational exposure. The median age was 70 years and 62% of the patients were men. In univariate analyses, we found relationships between MDS and smoking habits, gardening, occupations such as health professionals, technical and sale representatives, machine operators, agricultural workers, textile workers, qualitative occupational exposures (exposed/non-exposed) to oil, solvents, ammonia, pesticides, fertilizers, cereal dusts, contact with poultry or livestock and infective risk, and lifetime cumulative exposure to solvents, oil, textile dust and infective risk. The main risk factors of MDS determined by multivariate analyses (conditional logistic regression) were, being an agricultural worker [odds ratio (OR) = 3·66; 95% confidence interval (CI) 1·9–7·0], textile operator (OR = 3·66; 95% CI 1·9–7·9), health professional (OR = 10·0; 95% CI 2·1–48·7), commercial and technical sale representative (OR = 4·45; 95% CI 1·4–14·6), machine operator (OR = 2·69; 95% CI 1·2–6·0), living next to an industrial plant (OR = 2·45; 95% CI 1·5–4·1), smoking (OR = 1·74; 95% CI 1·1–2·7) and lifetime cumulative exposure to oil (OR = 1·1; 95% CI 1·0–1·2). Further studies should be performed to assess specific exposures more precisely and it would be of interest to develop a map of haematological malignancies according to industrial background.
Article
Fewer than 10% of patients with myelodysplastic syndromes (MDS) are younger than 50 years. A series of 91 younger patients (median age 44 years with female prevalence) are reported and compared with elderly patients. Frequent karyotypic changes were trisomy 8 (9.8%) and monosomy 7 (5%). Twenty-three patients had occupational exposure to potential mutagens (benzene and solvents), with a male predominance, higher frequency of refractory cytopenia with multilineage dysplasia (RCMD) (52%) and higher frequency of monosomy 7 (21.7%). At a median follow-up of 72 months, 22 patients (24%) evolved to acute leukemia, with higher frequency being observed among the exposed cohort (39% vs. 19% non-exposed). Unfavorable factors for overall survival were: age > 40 years, > 5% of blasts, trilinear bone marrow involvement and intermediate-high World Health Organization Prognostic Scoring System (WPSS) risk. The present results suggest that younger MDS could be identified as a distinct subset. For patients belonging to the low/intermediate-I risk group, due to a low transformation rate, aggressive approaches should rarely be recommended.
Article
Spatial cluster modelling of small area disease incidence and mortality has previously focused on clusters where excess risk is distributed around fixed points, and the aim is the reconstruction of these points (cluster centers). Often there is a need to assess clusters of a different form, such as around roads or river systems. These clusters are often linear or can be approximated by combinations of several linear segments. In this paper the recovery of point and line clusters is considered jointly. An example application is given where both linear or point clustering could be present.
Article
Many different methods have been proposed to test for geographical disease clustering, and more generally, for spatial clustering of any type of observations while adjusting for an inhomogeneous background population generating the observations. Despite the many proposed test statistics, there has been few formal comparisons conducted. We present a collection of 1,220,000 simulated benchmark data sets generated under 51 different cluster models and the null hypothesis, to be used for power evaluations. We then use these data sets to compare the power of the spatial scan statistic, the maximized excess events test and the nonparametric M statistic. All have good power, the first having an advantage for localized hot-spot type clusters and the second for global clustering where randomly located cases generate other cases close by. By making the simulated data sets publicly available, new tests can easily be compared with previously evaluated tests by analyzing the same benchmark data.
Article
The myelodysplastic syndromes (MDS) are a collection of hematologic disorders that affect older adults, and whose baseline characteristics and risk factors for evolution to acute myeloid leukemia (AML) and death have not been completely defined. We analyzed a large unselected cohort of 214 patients with MDS from the University of Pittsburgh Network Cancer Registry in Western Pennsylvania. Patients' follow-up was 22 months, at the end of which 72.9% of patients were dead. Overall, the 36-month survival rate was 19.0% (95% CI: 14.0-24.5%); 22.4% (95% CI: 16.4-29.0%) for patients with lower-risk MDS; and 5.0% (95% CI: 0.1-14.8%) for patients with higher-risk MDS (p = 0.0007). During follow-up, 32.9% of the patients developed AML. Family history of cancer and having  ≥5% blasts at diagnosis were statistically significant predictors for progression to AML. A higher risk of death also was associated with age >70 years and previous diagnosis of another cancer. More than three cycles of chemotherapy sessions and a platelet count of ≥50 × 10(3)/mm(3) were inversely associated with death. This study suggests the need to incorporate laboratory results such as percentage blasts and platelet counts as well as epidemiologic data on family history of cancer in future outcome studies on MDS.
Article
A case-control study of newly diagnosed myelodysplastic syndrome patients investigated lifetime exposures through occupation, environment or hobby by questionnaire, structured and semi-structured interview. The exposure histories of 400 individually matched pairs were compared. Increased or possibly increased odds ratios were observed for radiation (2.05, 95% confidence interval 1.16-3.76), halogenated organics (1.57, 0.97-2.57), metals (1.40, 0.99-2.00), several specific radiation exposures and individual chemicals and for childlessness (1.46, 1.01-2.11). Since myelodysplasia generally carries a poor prognosis, whether or not individuals convert to leukaemia or to other cancer, these findings add to previous reports of exposures implicated in the aetiology of leukaemia and add to the case for minimizing exposures to radiation and halogenated organics.
Article
This article presents a space-time scan statistic, useful for evaluating space-time cluster alarms, and illustrates the method on a recent brain cancer cluster alarms in Los Alamos, NM. The space-time scan statistic accounts for the preselection bias and multiple testing inherent in a cluster alarm. Confounders and time trends can be adjusted for. The observed excess of brain cancer in Los Alamos was not statistically significant. The space-time scan statistic is useful as a screening tool for evaluating which cluster alarms merit further investigation and which clusters are probably chance occurrences.
Article
The prognostic impact of karyotypic patterns in a consecutive series of 389 adult myelodysplastic syndromes (MDS) was investigated. Time period did not significantly influence the survival times. In the analyses, the MDS cases were subdivided into the cytogenetic subgroups used in the International Prognostic Scoring System, i.e. favourable [-Y, del(5q) or del(20q) as single aberrations or normal karyotype, n = 241], poor [-7, del(7q), der(1;7) or complex karyotypes, i.e. > or = three abnormalities, n = 89] and intermediate (other aberrations, n = 59). The survival times correlated well with the prognostic subgroups, confirming that the cytogenetic classification was valid. Expressed as hazard ratios (HRs), with the favourable subgroup as the reference, the intermediate and poor subgroup HRs increased to 1.5 (95% confidence interval, 1.1-2.1) and 3.2 (2.4-4.1) respectively. Sex, age, morphological subtype and smoking habits significantly modified this prognostic impact. Shorter survival was detected for men in the favourable and the intermediate subgroups, but not in the poor prognosis subgroup. Using women in the favourable subgroup as the reference and adjusting for age, the HR for men was 1.6 (1.2-2.1) in the favourable subgroup. Adjusting for smoking habits as well decreased the HR to 1.4 (1.1-2.0) and, when also excluding cases with del(5q) as the sole anomaly, no significant difference could be discerned [HR 1.2 (0.9-1.6], suggesting that the better outcome for women in the favourable subgroup was mainly as a result of the '5q-syndrome' and to smoking habits. In the intermediate subgroup, the corresponding HRs were 3.0 (1.5-6.0) when adjusted for age and 2.7 (1.3-5.5) when also adjusted for smoking habits. Different survival times between men and women have never previously been reported for this MDS group. Although it remains to be elucidated whether environmental and/or constitutional factors cause the observed sex-related difference, these observations have obvious clinical ramifications, not least in designing and evaluating therapy protocols.
Article
The myelodysplastic syndrome (MDS) includes a diverse group of clonal and potentially malignant bone marrow disorders characterized by ineffective and inadequate hematopoiesis. The presumed source of MDS is a genetically injured early marrow progenitor cell or pluripotential hematopoietic stem cell. The blood dyscrasias that fall under the broad diagnostic rubric of MDS appear to be quite heterogeneous, which has made it very difficult to construct a coherent, universally applicable MDS classification scheme. A recent re-classification proposal sponsored by the World Health Organization (WHO) has engendered considerable controversy. Although the precise incidence of MDS is uncertain, it has become clear that MDS is at least as common as acute myelogenous leukemia (AML). There is considerable overlap between these two conditions, and the former often segues into the latter; indeed, the distinction between AML and MDS can be murky, and some have argued that the current definitions are arbitrary. Despite the discovery of several tantalizing pathophysiological clues, the basic biology of MDS is incompletely understood. Treatment at present is generally frustrating and ineffective, and except for the small subset of patients who exhibit mild marrow dysfunction and low-risk cytogenetic lesions, the overall prognosis remains rather grim. In this narrative review, we highlight recent developments and controversies within the context of current knowledge about this mysterious and fascinating cluster of bone marrow failure states.
Article
Little is known about the etiology of myelodysplastic syndromes (MDS). A hospital-based case-control study of 354 adult de novo MDS cases and 452 controls was conducted to investigate associations between lifestyle characteristics and MDS risk. The distribution by French-American-British (FAB) type was 67 (19%) refractory anemia (RA), 38 (11%) refractory anemia with ringed sideroblasts (RARS), 43 (12%) chronic myelomonocytic leukemia (CMML), 136 (38%) RA with excess blasts (RAEB), and 70 (20%) RAEB in transformation (RAEBT). Multivariate logistic regression analyses were performed among all MDS cases and among each FAB type and gender. For all MDS combined, family history of hematopoietic cancer (odds ratio (OR) = 1.92), smoking (OR = 1.65), and exposure to agricultural chemicals (OR = 4.55) or solvents (OR = 2.05) were associated with MDS risk. Among RA/RARS cases, smoking (OR = 2.23) and agricultural chemical exposure (OR = 5.68) were the only risk factors identified. For RAEB/RAEBT cases, family history of hematopoietic cancer (OR = 2.10), smoking (OR = 1.52), and exposure to agricultural chemicals (OR = 3.79) or solvents (OR = 2.71) were independent risk factors. Drinking wine reduced risk for all FAB types by almost 50% (OR = 0.54). We found a joint effect between smoking and chemical exposure with the highest risk among smokers exposed to solvents/agricultural chemicals (OR = 3.22). Results from this large study suggest that several factors play a role in MDS predisposition with possible joint effects. Risk profiles seem to differ by FAB type and gender.
Article
Myelodysplastic syndromes (MDS) became reportable to the Surveillance, Epidemiology, and End Results (SEER) Program (the United States cancer surveillance program) in 2001. This provided the first opportunity to examine the incidence and survival of patients with MDS in the United States using a large, population-based database. The SEER 17 regions public-use database (November 2005 submission) was accessed to obtain data on the frequency, incidence, and survival of patients with MDS. Geographic areas were selected for inclusion in the SEER Program based on their ability to operate and maintain a high-quality, population-based cancer reporting system and for their epidemiologically significant population subgroups. SEER data from 2001 through 2003 indicated that the risk of MDS increased with age, and approximately 86% of MDS cases were diagnosed in individuals aged > or =60 years (median age at diagnosis = 76 years). Men had a significantly higher incidence rate than women (4.5 vs 2.7 per 100,000 per year). Among racial groups, white individuals had the highest incidence rate. In 2003, approximately 10,300 incident cases of MDS were diagnosed in the United States. The survival of MDS patients was poor, with an observed 3-year survival rate of only 35% (5-year survival data were not available at the time of the current report). Male patients and patients who were diagnosed at an older age had significantly worse survival. MDS survival also varied by clinical subtype, and the survival of patients who had refractory anemia was somewhat worse than reported previously. The availability of descriptive epidemiologic data on MDS can be used now to facilitate much needed research on the etiology and outcome of MDS. The current results indicated that >10,000 incident cases of MDS are diagnosed annually in the United States, and the survival of patients with MDS is poor. The availability of descriptive epidemiologic data on MDS can be used now to facilitate much needed research on the etiology and outcomes of MDS.
Article
The myelodysplastic syndromes (MDS) are a group of malignancies with poor prognosis and obscure etiology. To better understand the distribution of MDS in the population and help generate etiologic hypotheses, we assessed potential clustering in the incidence of MDS in the state of Connecticut using population-based cancer registry data that recently became available. A significant spatial clustering was identified. The most likely area with a high incidence of MDS included 46 census tracts near the west border of Connecticut, and the ratio of observed/expected cases was 2.84. The P value associated with this cluster was 0.0001. Although no temporal clustering was indicated, a space-time analysis identified a cluster in the central south of Connecticut from March 2002 through August 2003 (P=0.008). This is the first analysis of potential clustering in the incidence of MDS using population-based data. If the intriguing finding on spatial clustering is supported by future studies with larger sample sizes and/or in other geographic areas, it would be extremely interesting to explore the "causes" of clustering, which may help shed light on the etiology of MDS.
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