5-Aza-2 ¶-deoxycytidine (decitabine) is postulated to have clinical activity in myeloid leukemias via its ability to inhibit DNA methylation. To study this, we examined DNA methylation in patients with leukemia treated with decitabine. Five days after the treatment, total genomic 5-methylcytosine/ cytosine decreased on average by 14% ( from 4.3% to 3.7%), whereas methylation of repetitive DNA elements showed a mean decrease of 9% and 16% for Alu and long interspersed nucleotide elements, respectively. Methylation decreased linearly with increasing doses between 5 and 20 mg/m 2 /d (r = 0.88; P = 0.05) but showed a plateau above that. Hypomethylation correlated with response in patients with acute myelogenous leukemia treated with low doses (5-20 mg/m 2 /d), but patients with chronic myelogenous leukemia treated with high doses (100-180 mg/m 2 /d) showed no such correlation. Aberrant methylation of p15 (>10%) was found in 27% of patients, and 80% of these showed a decrease by at least one third, but this did not correlate with response. The imprinted gene H19 showed little change in methylation after decitabine. In conclusion, we show dose-dependent hypomethylation after decitabine at low doses. Increasing the dose, which has been shown previously to result in a reduced response rate, was not accompanied by further hypomethylation. (Cancer Res 2006; 66(10): 5495-503)
Chronic conditions and related functional disabilities are highly prevalent among resettled refugees in the United States. There is a need to explore this population's access to appropriate healthcare services in order to identify service disparities and improve interventions. Using a community-based participatory research approach, semi-structured interviews were conducted with key informants to identify healthcare access barriers affecting disabled and chronically ill refugees. Eighteen participants were interviewed, revealing three main barriers: (1) inadequate health insurance, (2) language and communication barriers, and (3) a complex maze of service systems. These barriers were found to operate at systems, provider, and individual levels. Broad-based policy and practice interventions are required to address barriers including: an expanded pool of medical interpreters, peer navigators, innovative health information technologies, and greater collaboration and information-sharing between service systems. Further research is needed to monitor the impact the Affordable Care Act on service access of refugees with disabilities and chronic conditions.
Carcinoid tumors and pancreatic endocrine tumors are uncommon neuroendocrine neoplasms, and their genetic alterations are not well characterized. These tumors have site-specific differences in neuroendocrine characteristics, clinical course and genetic alterations. We compared clinicopathological features and loss of heterozygosity of chromosomes 11q, 16q and 18, and BRAF gene mutations in 47 patients with neuroendocrine tumors including 16 with pancreatic endocrine tumors, 15 with nonileal carcinoid tumors and 16 with ileal carcinoid tumors. Patients with carcinoid tumors had more frequent history of alcohol consumption compared to patients with pancreatic endocrine tumors (P ¼ 0.02), and patients with ileal carcinoid tumors more frequently had liver metastasis compared to patients with nonileal carcinoid tumors and pancreatic endocrine tumors (P ¼ 0.02). Allelic loss of chromosome 11q was present in 21% of tumors, chromosome 16q in 13%, and chromosome 18 in 30%. These alterations differed with the anatomical subsite of tumor: allelic loss of chromosome 18 was present in 69% of ileal carcinoid tumors, 13% of nonileal carcinoid tumors and 6% of pancreatic endocrine tumors (P ¼ 0.001). In contrast to pancreatic endocrine tumors and nonileal carcinoid tumors, all 11 ileal tumors with loss of chromosome 18 had complete loss of both chromosomal arms. No BRAF mutations were identified. Complete allelic loss of chromosome 18 was associated with smaller tumor size (P ¼ 0.02). Our study indicates that genetic alterations vary by tumor subsite and clinicopathologic features, and ileal carcinoid tumors have distinctive clinicopathologic and genetic profiles.
Supplementary Table 1 and Figure 1 from DNA Methylation Changes after 5-Aza-2′-Deoxycytidine Therapy in Patients with Leukemia
<div>Abstract<p>5-Aza-2′-deoxycytidine (decitabine) is postulated to have clinical activity in myeloid leukemias via its ability to inhibit DNA methylation. To study this, we examined DNA methylation in patients with leukemia treated with decitabine. Five days after the treatment, total genomic 5-methylcytosine/cytosine decreased on average by 14% (from 4.3% to 3.7%), whereas methylation of repetitive DNA elements showed a mean decrease of 9% and 16% for <i>Alu</i> and long interspersed nucleotide elements, respectively. Methylation decreased linearly with increasing doses between 5 and 20 mg/m<sup>2</sup>/d (<i>r</i> = 0.88; <i>P</i> = 0.05) but showed a plateau above that. Hypomethylation correlated with response in patients with acute myelogenous leukemia treated with low doses (5-20 mg/m<sup>2</sup>/d), but patients with chronic myelogenous leukemia treated with high doses (100-180 mg/m<sup>2</sup>/d) showed no such correlation. Aberrant methylation of <i>p15</i> (>10%) was found in 27% of patients, and 80% of these showed a decrease by at least one third, but this did not correlate with response. The imprinted gene <i>H19</i> showed little change in methylation after decitabine. In conclusion, we show dose-dependent hypomethylation after decitabine at low doses. Increasing the dose, which has been shown previously to result in a reduced response rate, was not accompanied by further hypomethylation. (Cancer Res 2006; 66(10): 5495-503)</p></div>
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