Epidemiology of secondary leukemia with reference to chromosomal abnormalities

Secondary acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) have been recognized as one of the most feared long-term complications of cancer therapy. The aim of this case-control study was to determine the prevalence of chromosomal abnormalities and family history of cancer among secondary AML/MDS cases and de novo AML/MDS controls. Study population were 332 MD Anderson Cancer Center patients who were registered between 1986 and 1994. Cases were patients who had a prior invasive cancer before diagnoses of AML/MDS and controls were de novo AML/MDS. Cases (166) and controls (166) were frequency matched on age $\pm$5 years, sex and year of diagnosis of leukemia. Cytogenetic data were obtained from the leukemia clinic database of MD Anderson Cancer Center and data on family history of cancer and other risk factors were abstracted from the patients' medical record. The distribution of AML and MDS among cases was 58% and 42% respectively and among controls 67% and 33% respectively. Prevalence of chromosomal abnormalities were observed more frequently among cases than controls. Reporting of family history of cancer were similar among both groups. Univariate analysis revealed an odds ratio (OR) of 2.8 (95% CI 1.5-5.4) for deletion of chromosome 7, 1.9 (95% CI 0.9-3.8) for deletion of chromosome 5, 2.3 (95% CI 0.8-6.2) for deletion of 5q, 2.0 (95% CI 1.0-4.2) for trisomy 8, 1.3 (95% CI 0.8-2.1) for chromosomal abnormalities other than chromosome 5 or 7 and 1.3 (95% CI 0.8-2.0) for family history of cancer in a first degree relative. The OR remained significant for deletion of chromosome 7 (2.3, 95% CI 1.1-4.8) after adjustment for age, alcohol, smoking, occupation related to chemical exposure and family history of cancer in a first degree relative. Of the 166 secondary AML/MDS patients 70% had a prior solid tumor and 30% experienced hematological cancers. The most frequent cancers were breast (21.1%), non-Hodgkin lymphoma (13.3%), Hodgkin's disease (10.2%), prostate (7.2%), colon (6%), multiple myeloma (3.6%) and testes (3.0%). The majority of these cancer patients were treated with chemotherapy or radiotherapy or both. Abnormalities of chromosome 5 or 7 were found to be more frequent in secondary AML/MDS patients with prior hematological cancer than patients with prior solid tumors. Median time to develop secondary AML/MDS was 5 years. However, secondary AML/MDS among patients who received chemotherapy and had a family history of cancer in a first degree relative occurred earlier (median 2.25 $\pm$ 0.9 years) than among patients without such family history (median 5.50 $\pm$ 0.18 years) (p $<$.03). The implication of exposure to chemotherapy among patients with a family history of cancer needs to be further investigated. ^

A novel myeloid leukemia suppressor locus at human chromosome 5q13.3

Molecular mechanisms that underlie preleukemic myelodysplasia (MDS) and acute myelogenous leukemia (AML) are poorly understood. In MDS or AML with a refractory clinical course, more than 30% of patients have acquired interstitial or complete deletions of chromosome 5. The 5q13.3 chromosomal segment is commonly lost as the result of 5q deletion. Reciprocal and unbalanced translocations of 5q13.3 can also occur as sole anomalies associated with refractory AML or MDS. This study addresses the hypothesis that a critical gene at 5q13.3 functions either as a classical tumor suppressor or as a chromosomal translocation partner and contributes to leukemogenesis. ^ Previous studies from our laboratory delineated a critical region of loss to a 2.5–3.0Mb interval at 5q13.3 between microsatellite markers D5S672 and GATA-P18104. The critical region of loss was later resolved to an interval of approximately 2Mb between the markers D5S672 and D5S2029. I, then generated a long range physical map of yeast artificial chromosomes (YACs) and developed novel sequence tagged sites (STS). To enhance the resolution of this map, bacterial artificial chromosomes (BACs) were used to construct a triply linked contig across a 1 Mb interval. These BACs were used as probes for fluorescent in situ hybridization (FISH) on an AML cell line to define the 5q13.3 critical region. A 200kb BAC, 484a9, spans the translocation breakpoint in this cell line. A novel gene, SSDP2 (single stranded DNA binding protein), is disrupted at the breakpoint because its first four exons are encoded within 140kb of BAC 484a9. This finding suggests that SSDP2 is the critical gene at 5q13.3. ^ In addition, I made an observation that deletions of chromosome 5q13 co-segregate with loss of the chromosome 17p. In some cases the deletions result from unbalanced translocations between 5q13 and 17p13. It was confirmed that the TP53 gene is deleted in patients with 17p loss, and the remaining allele harbors somatic mutation. Thus, the genetic basis for the aggressive clinical course in AML and MDS may be caused by functional cooperation between deletion or disruption of the 5q13.3 critical gene and inactivation of TP53. ^

Maximizing efficacy of the hypomethylating drug 5-aza-2'-deoxycytidine in human leukemia

5-aza-2'-deoxycytidine (DAC) is a cytidine analogue that strongly inhibits DNA methylation, and was recently approved for the treatment of myelodysplastic syndromes (MDS). To maximize clinical results with DAC, we investigated its use as an anti-cancer drug. We also investigated mechanisms of resistance to DAC in vitro in cancer cell lines and in vivo in MDS patients after relapse. We found DAC sensitized cells to the effect of 1-β-D-Arabinofuranosylcytosine (Ara-C). The combination of DAC and Ara-C or Ara-C following DAC showed additive or synergistic effects on cell death in four human leukemia cell lines in vitro, but antagonism in terms of global methylation. RIL gene activation and H3 lys-9 acetylation of short interspersed elements (Alu). One possible explanation is that hypomethylated cells are sensitized to cell killing by Ara-C. Turning to resistance, we found that the IC50 of DAC differed 1000 fold among and was correlated with the dose of DAC that induced peak hypomethylation of long interspersed nuclear elements (LINE) (r=0.94, P<0.001), but not with LINE methylation at baseline (r=0.05, P=0.97). Sensitivity to DAC did not significantly correlate with sensitivity to another hypomethylating agent 5-azacytidine (AZA) (r=0.44, P=0.11). The cell lines most resistant to DAC had low dCK, hENT1, and hENT2 transporters and high cytosine deaminase (CDA). In an HL60 leukemia cell line, resistance to DAC could be rapidly induced by drug exposure, and was related to a switch from monoallelic to biallelic mutation of dCK or a loss of wild type DCK allele. Furthermore, we showed that DAC induced DNA breaks evidenced by histone H2AX phosphorylation and increased homologous recombination rates 7-10 folds. Finally, we found there were no dCK mutations in MDS patients after relapse. Cytogenetics showed that three of the patients acquired new abnormalities at relapse. These data suggest that in vitro spontaneous and acquired resistance to DAC can be explained by insufficient incorporation of drug into DNA. In vivo resistance to DAC is likely due to methylation-independent pathways such as chromosome changes. The lack of cross resistance between DAC and AZA is of potential clinical relevance, as is the combination of DAC and Ara-C. ^

A comparative analysis of CHIP Perinatal policy in twelve states

The purpose of this comparative analysis of CHIP Perinatal policy (42 CFR § 457) was to provide a basis for understanding the variation in policy outputs across the twelve states that, as of June 2007, implemented the Unborn Child rule. This Department of Health and Human Services regulation expanded in 2002 the definition of “child” to include the period from conception to birth, allowing states to consider an unborn child a “targeted low-income child” and therefore eligible for SCHIP coverage. ^ Specific study aims were to (1) describe typologically the structural and contextual features of the twelve states that adopted a CHIP Perinatal policy; (2) describe and differentiate among the various designs of CHIP Perinatal policy implemented in the states; and (3) develop a conceptual model that links the structural and contextual features of the adopting states to differences in the forms the policy assumed, once it was implemented. ^ Secondary data were collected from publicly available information sources to describe characteristics of states’ political system, health system, economic system, sociodemographic context and implemented policy attributes. I posited that socio-demographic differences, political system differences and health system differences would directly account for the observed differences in policy output among the states. ^ Exploratory data analysis techniques, which included median polishing and multidimensional scaling, were employed to identify compelling patterns in the data. Scaled results across model components showed that economic system was most closely related to policy output, followed by health system. Political system and socio-demographic characteristics were shown to be weakly associated with policy output. Goodness-of-fit measures for MDS solutions implemented across states and model components, in one- and two-dimensions, were very good. ^ This comparative policy analysis of twelve states that adopted and implemented HHS Regulation 42 C.F.R. § 457 contributes to existing knowledge in three areas: CHIP Perinatal policy, public health policy and policy sciences. First, the framework allows for the identification of CHIP Perinatal program design possibilities and provides a basis for future studies that evaluate policy impact or performance. Second, studies of policy determinants are not well represented in the health policy literature. Thus, this study contributes to the development of the literature in public health policy. Finally, the conceptual framework for policy determinants developed in this study suggests new ways for policy makers and practitioners to frame policy arguments, encouraging policy change or reform. ^

Evaluation of epidemiological and clinical factors in survival of patients with de novo myelodysplastic syndrome at the University of Texas MD Anderson cancer center

Little is known about epidemiological markers that are associated with survival of patients with myelodysplastic syndromes (MDS). We conducted a secondary case-based analysis of 465 de novo MDS patients from the University of Texas MD Anderson Cancer Center (UTMDACC). We investigated the association between demographic as well as occupational exposure markers and survival while incorporating known clinical markers of prognosis. In our patient population, 60.6% were men and the majority were white (93.1%). The distribution of MDS subtypes by the French–American–British (FAB) classification was 81 (19%) refractory anemia (RA), 46 (9.9%) refractory anemia with ringed sideroblasts (RARS), 57 (12.3%) chronic myelomonocytic leukemia (CMML), 173 (37.2%) RA with excess blasts (RAEB), and 86 (18.5%) RAEB in transformation (RAEBT). We found that those older at diagnosis (> 60 years of age) (HR = 1.68, CI = 1.26-2.25) were at a higher risk of dying compared to younger patients. Similarly, high pack years of smoking (>= 30 pack years of smoking) (HR = 1.34, CI = 1.02-1.74), and agricultural chemical exposure (HR = 1.61, CI = 1.05-2.46) were significantly associated with overall lower survival when compared to patients with none or medium exposures. Among clinical markers, greater than 5% bone marrow blasts (HR = 1.81 CI = 1.27-2.56), poor cytogenetics (HR = 3.20, CI = 2.37-4.33)), and platelet cytopenias (<100000/ul) (HR = 1.46, CI = 1.11-1.92) were also significantly associated with overall MDS survival.^ The identification of epidemiological markers could help physicians stratify patients and customize treatment strategies to improve the outcome of MDS based on patient lifestyle information such as smoking exposure and agrochemical exposure. We hope that this study highlights the impact of these exposures in MDS prognosis.^

Delays in diagnosis and referral and treatment for hematologic malignancies

The purpose of this thesis project was to identify factors that may contribute to a delay in the diagnosis, referral or treatment of the hematologic malignancies. This thesis is a secondary data analysis of both qualitative and quantitative data collected during a pilot study for a parent CDC study to determine factors related to time to diagnosis, referral, and treatment of chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), multiple myeloma (MM), and myelodisplastic syndrome (MDS). To identify patterns for referral, as well as explore referral, treatment, and follow-up patterns, MDACC performed a pathways analysis, and conducted semi-structured interviews with hematologic cancer patients to help identify factors related to delays. Interviews were also conducted with primary care physicians and community hematologists/oncologists to help identify factors associated with optimal and sub-optimal patterns of diagnosis and referral. The results of these analyses suggest a set of factors that may be related to a fairly smooth and rapid trajectory to treatment, and factors that may be related to a slower, more disrupted trajectory. Factors that may be especially important to facilitating rapid treatment include the presence of cues to seek diagnosis in the patient's environment and the patient recognizing and acting upon these cues to seek immediate medical attention. Furthermore, providers who perform behaviors including recognizing cues as indicators of hematologic malignancies and conducting appropriate diagnostic testing effectively and efficiently indicate that these behaviors may also contribute to shorter times to diagnosis. In regards to referrals, direct and effective communication between providers and patients, as well between providers themselves helped facilitate speedier referrals. A patient's insurance status as well as the presence or absence of social support in his environment served as factors that may increase or decrease time to diagnosis, referral, and treatment for a hematologic malignancy. Further research is needed to define delay to diagnosis, referral and treatment in order to improve early diagnosis, referral, and treatment of hematologic malignancies.^

Assessing the relationship between board composition and nonprofit hospital financial performance from a multi-theoretic perspective

This dissertation assesses the relationship between board composition and financial performance for the top 71 major nonprofit hospitals in the United States during the period 2004-2009. The underlying data were collected from copies of IRS Form 990 available at http://www.guidestar.org . The dissertation investigates five factors: board size, board independence (percentage of outsiders), number of MDs, CEO succession and CEO compensation. And it evaluates the results within a multi-theoretic framework drawing on agency theory, resource dependence theory, institutional theory and social network theory. Corporate governance literature suggests that board composition has an important impact on firm financial performance. This dissertation examines whether the same may be true for nonprofit hospitals. The results should help hospital executives make better governance decisions during trying economic times.^