The two types of intervention protocol well reflected the treatment intention and expected outcomes. Further, large-scale cohort studies are promising.
Continuous deep sedation until death (CDS) is a type of palliative sedation therapy, and it has recently become a focus of intense debate. Marked inconsistencies in intervention procedures (i.e., what is CDS?) and unstandardized descriptions of patient backgrounds lead to difficulty in comparing the results in the literature. The primary aim of this article was to propose a conceptual framework to perform empirical studies on CDS. We propose the definition of CDS using the intervention protocol. As there are two types of CDS proposed in world-wide literature, we recommend to prepare two types of intervention protocol for CDS: "continuous deep sedation as a result of proportional sedation" (gradual CDS) and "continuous deep sedation to rapidly induce unconsciousness" (rapid CDS). In addition, we recommend that researchers characterize study patients' general condition using a validated prognostic tool, Prognosis in Palliative Care Study predictor model-A. Using this conceptual framework, we can compare the outcomes following the same exposures among homogenous patients throughout the world. This article proposes a provisional definition of two types of CDS. Defining CDS using the intervention protocol and describing patient backgrounds using validated prognostic tools enable comparisons and interpretations of empirical research about CDS. More empirical studies are urgently needed.
Global DNA hypomethylation is a characteristic feature of cancer cells that closely associates with chromosomal instability (CIN). However, the association between these characteristics during hepatocarcinogenesis remains unclear. Herein, we determined the relationship between hypomethylation and CIN in human hepatocellular carcinoma (HCC) by analyzing 179 HCCs, 178 matched non-tumor livers and 23 normal liver tissues. Hypomethylation at three different repetitive DNA (rDNA) sequences and hypermethylation of 12 CpG loci, including 11 tumor suppressor gene (TSG) promoters, were quantified using MethyLight or combined bisulfite restriction analysis. Fractional allelic loss (FAL) was used as a marker for CIN, calculated by analyzing 400 microsatellite markers. Gains and losses at each chromosome were also determined using semi-quantitative microsatellite analysis. The associations between rDNA hypomethylation and FAL, as well as between TSG hypermethylation and FAL were investigated. Significantly more hypomethylation was observed in HCC tissues than in normal liver samples. Progression of hypomethylation during carcinogenesis was more prominent in hepatitis C virus (HCV)-negative cases, which was in contrast to our previous reports of significantly increased TSG methylation levels in HCV-positive tumors. Absence of liver cirrhosis and higher FAL scores were identified as independent contributors to significant hypomethylation of rDNA in HCC. Among the chromosomal alterations frequently observed in HCC, loss of 8p, which was unique in the earliest stages of hepatocarcinogenesis, was significantly associated with hypomethylation of rDNA by multivariable analysis (p = 0.0153). rDNA hypomethylation was also associated with a high FAL score regardless of tumor differentiation (p = 0.0011, well-differentiated; p = 0.0089, moderately/poorly-differentiated HCCs). We conclude that DNA hypomethylation is an important cause of CIN in the earliest step of HCC, especially in a background of non-cirrhotic liver.
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